Professor Hardev Pandha
Professor of Medical Oncology
Academic and research departments
School of Biosciences and Medicine, Faculty of Health and Medical Sciences.Biography
Hardev Pandha is a clinician scientist and medical oncologist who graduated in medicine at the University of Birmingham. He trained in internal medicine and subsequently in medical oncology at the Royal Postgraduate Medical School at Hammersmith Hospital, London. He completed his PhD (Imperial College) in the Imperial Cancer Research Fund labs at the Hammersmith. He was a visiting fellow at Stanford University prior to completing his medical oncology training at the Royal Marsden Hospital, London. He was a senior lecturer in tumour immunology and medical oncology at St Georges, University of London in 2000 before being appointed Prof of Urological Oncology at the University of Surrey in 2006.
His areas of expertise include the management of patients with Urological cancers and malignant melanoma. He has a key interest in early phase clinical trials involving targeted agents and the translational aspects of novel therapies. His portfolio includes gene and viral therapy as well as immunotherapy and small molecule inhibitors. His laboratory interests reflect this and in particular a combination of novel and biological therapies with more conventional treatments. His lab team have evolved a robust infrastructure of patient sample procurement and biobanking for translational research.
Research
Research interests
- Tumour immunology
- Urological cancer
- Gene therapy
My publications
Highlights
- The Role of Circular RNAs in Pancreatic Ductal Adenocarcinoma and Biliary-Tract Cancers. Limb C, Liu DSK, Veno MT, Rees E, Krell J, Bagwan IN, Giovannetti E, Pandha H, Strobel O, Rockall TA, Frampton AE.Limb C, et al. Cancers (Basel). 2020 Nov 4;12(11):E3250.
- An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk. Wu L, Yang Y, Guo X, Shu XO, Cai Q, Shu X, Li B, Tao R, Wu C, Nikas JB, Sun Y, Zhu J, Roobol MJ, Giles GG, Brenner H, John EM, Clements J, Grindedal EM, Park JY, Stanford JL, Kote-Jarai Z, Haiman CA, Eeles RA, Zheng W, Long J; PRACTICAL consortium; CRUK Consortium; BPC3 Consortium; CAPS Consortium; PEGASUS Consortium.Wu L, et al. Nat Commun. 2020 Aug 6;11(1):3905.
- A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data. Huynh-Le MP, Fan CC, Karunamuni R, Walsh EI, Turner EL, Lane JA, Martin RM, Neal DE, Donovan JL, Hamdy FC, Parsons JK, Eeles RA, Easton DF, Kote-Jarai Z, Amin Al Olama A, Benlloch Garcia S, Muir K, Grönberg H, Wiklund F, Aly M, Schleutker J, Sipeky C, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Pharoah PDP, Pashayan N, Khaw KT, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Wokolorczyk D, Kluzniak W, Cannon-Albright LA, Brenner H, Schöttker B, Holleczek B, Park JY, Sellers TA, Lin HY, Slavov CK, Kaneva RP, Mitev VI, Batra J, Clements JA, Spurdle AB, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Mills IG, Andreassen OA, Dale AM, Seibert TM; Australian Prostate Cancer BioResource (APCB); PRACTICAL Consortium.Huynh-Le MP, et al. Cancer Epidemiol Biomarkers Prev. 2020 Sep;29(9):1731-1738.
- The effect of sample size on polygenic hazard models for prostate cancer. Karunamuni RA, Huynh-Le MP, Fan CC, Eeles RA, Easton DF, Kote-Jarai Z, Amin Al Olama A, Benlloch Garcia S, Muir K, Gronberg H, Wiklund F, Aly M, Schleutker J, Sipeky C, Tammela TLJ, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw KT, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Wokolorczyk D, Kluzniak W, Cannon-Albright L, Brenner H, Schöttker B, Holleczek B, Park JY, Sellers TA, Lin HY, Slavov C, Kaneva R, Mitev V, Batra J, Clements JA, Spurdle A; Australian Prostate Cancer BioResource (APCB), Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Mills IG, Andreassen OA, Dale AM, Seibert TM; PRACTICAL Consortium.Karunamuni RA, et al. Eur J Hum Genet. 2020 Oct;28(10):1467-1475.
- Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan. Hollis B, Day FR, Busch AS, Thompson DJ, Soares ALG, Timmers PRHJ, Kwong A, Easton DF, Joshi PK, Timpson NJ; PRACTICAL Consortium; 23andMe Research Team, Ong KK, Perry JRB.Hollis B, et al.Nat Commun. 2020 Mar 24;11(1):1536.
- Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response. Annels NE, Simpson GR, Pandha H.Annels NE, et al. Front Oncol. 2020 Feb 18;10:175
- The PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent Mechanism. McLaughlin M, Pedersen M, Roulstone V, Bergerhoff KF, Smith HG, Whittock H, Kyula JN, Dillon MT, Pandha HS, Vile R, Melcher AA, Harrington KJ.McLaughlin M, et al. Mol Ther Oncolytics. 2020 Jan 17;16:238-249.
- Rationale and design of the POLEM trial: avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III mismatch repair deficient or POLE exonuclease domain mutant colon cancer: a phase III randomised study. Lau D, Kalaitzaki E, Church DN, Pandha H, Tomlinson I, Annels N, Gerlinger M, Sclafani F, Smith G, Begum R, Crux R, Gillbanks A, Wordsworth S, Chau I, Starling N, Cunningham D, Dhillon T.Lau D, et al. ESMO Open. 2020 Feb;5(1):e000638.
- PBX3 in Cancer. Morgan R, Pandha HS.Morgan R, et al. Cancers (Basel). 2020 Feb 13;12(2):431.
- APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy. Driscoll CB, Schuelke MR, Kottke T, Thompson JM, Wongthida P, Tonne JM, Huff AL, Miller A, Shim KG, Molan A, Wetmore C, Selby P, Samson A, Harrington K, Pandha H, Melcher A, Pulido JS, Harris R, Evgin L, Vile RG.Driscoll CB, et al.. Nat Commun. 2020 Feb 7;11(1):790.
- A Specific Blood Signature Reveals Higher Levels of S100A12: A Potential Bladder Cancer Diagnostic Biomarker Along With Urinary Engrailed-2 Protein Detection. Elamin AA, Klunkelfuß S, Kämpfer S, Oehlmann W, Stehr M, Smith C, Simpson GR, Morgan R, Pandha H, Singh M. Front Oncol. 2020 Jan 9;9:1484.
- The Open University's first one-day symposium on treatment-emergent neuroendocrine prostate cancer. Mather RL, Andrews H, Pandha H, Jachetti E, Micallef J, Wang Y, Crea F. Future Oncol. 2020 Feb;16(6):147-149.
Publications
David V Conti, Burcu F Darst, Lilit C Moss, Edward J Saunders, Xin Sheng, Alisha Chou, Fredrick R Schumacher, Ali Amin Al Olama, Sara Benlloch, Tokhir Dadaev, Mark N Brook, Ali Sahimi, Thomas J Hoffmann, Atushi Takahashi, Koichi Matsuda, Yukihide Momozawa, Masashi Fujita, Kenneth Muir, Artitaya Lophatananon, Loic Le Marchand, Peggy Wan, Lynne R Wilkens, Victoria L Stevens, Susan M Gapstur, Brian D Carter, Johanna Schleutker, Teuvo L J Tammela, Csilla Sipeky, Anssi Auvinen, Graham G Giles, Melissa C Southey, Robert J MacInnis, Cezary Cybulski, Dominika Wokołorczyk, Jan Lubiński, David E Neal, Jenny L Donovan, Freddie C Hamdy, Richard M Martin, Børge G Nordestgaard, Sune F Nielsen, Maren Weischer, Stig E Bojesen, Martin Andreas Røder, Peter Iversen, Jyotsna Batra, Suzanne Chambers, Leire Moya, Lisa Horvath, Judith A Clements, Wayne Tilley, Gail P Risbridger, Henrik Gronberg, Markus Aly, Robert Szulkin, Martin Eklund, Tobias Nordström, Nora Pashayan, Alison M Dunning, Maya Ghoussaini, Ruth C Travis, Tim J Key, Elio Riboli, Jong Y Park, Thomas A Sellers, Hui-Yi Lin, Demetrius Albanes, Stephanie J Weinstein, Lorelei A Mucci, Edward Giovannucci, Sara Lindstrom, Peter Kraft, David J Hunter, Kathryn L Penney, Constance Turman, Catherine M Tangen, Phyllis J Goodman, Ian M Thompson, Jr, Robert J Hamilton, Neil E Fleshner, Antonio Finelli, Marie-Élise Parent, Janet L Stanford, Elaine A Ostrander, Milan S Geybels, Stella Koutros, Laura E Beane Freeman, Meir Stampfer, Alicja Wolk, Niclas Håkansson, Gerald L Andriole, Robert N Hoover, Mitchell J Machiela, Karina Dalsgaard Sørensen, Michael Borre, William J Blot, Wei Zheng, Edward D Yeboah, James E Mensah, Yong-Jie Lu, Hong-Wei Zhang, Ninghan Feng, Xueying Mao, Yudong Wu, Shan-Chao Zhao, Zan Sun, Stephen N Thibodeau, Shannon K McDonnell, Daniel J Schaid, Catharine M L West, Neil Burnet, Gill Barnett, Christiane Maier, Thomas Schnoeller, Manuel Luedeke, Adam S Kibel, Bettina F Drake, Olivier Cussenot, Géraldine Cancel-Tassin, Florence Menegaux, Thérèse Truong, Yves Akoli Koudou, Esther M John, Eli Marie Grindedal, Lovise Maehle, Kay-Tee Khaw, Sue A Ingles, Mariana C Stern, Ana Vega, Antonio Gómez-Caamaño, Laura Fachal, Barry S Rosenstein, Sarah L Kerns, Harry Ostrer, Manuel R Teixeira, Paula Paulo, Andreia Brandão, Stephen Watya, Alexander Lubwama, Jeannette T Bensen, Elizabeth T H Fontham, James Mohler, Jack A Taylor, Manolis Kogevinas, Javier Llorca, Gemma Castaño-Vinyals, Lisa Cannon-Albright, Craig C Teerlink, Chad D Huff, Sara S Strom, Luc Multigner, Pascal Blanchet, Laurent Brureau, Radka Kaneva, Chavdar Slavov, Vanio Mitev, Robin J Leach, Brandi Weaver, Hermann Brenner, Katarina Cuk, Bernd Holleczek, Kai-Uwe Saum, Eric A Klein, Ann W Hsing, Rick A Kittles, Adam B Murphy, Christopher J Logothetis, Jeri Kim, Susan L Neuhausen, Linda Steele, Yuan Chun Ding, William B Isaacs, Barbara Nemesure, Anselm J M Hennis, John Carpten, Hardev Pandha, Agnieszka Michael, Kim De Ruyck, Gert De Meerleer, Piet Ost, Jianfeng Xu, Azad Razack, Jasmine Lim, Soo-Hwang Teo, Lisa F Newcomb, Daniel W Lin, Jay H Fowke, Christine Neslund-Dudas, Benjamin A Rybicki, Marija Gamulin, Davor Lessel, Tomislav Kulis, Nawaid Usmani, Sandeep Singhal, Matthew Parliament, Frank Claessens, Steven Joniau, Thomas Van den Broeck, Manuela Gago-Dominguez, Jose Esteban Castelao, Maria Elena Martinez, Samantha Larkin, Paul A Townsend, Claire Aukim-Hastie, William S Bush, Melinda C Aldrich, Dana C Crawford, Shiv Srivastava, Jennifer C Cullen, Gyorgy Petrovics, Graham Casey, Monique J Roobol, Guido Jenster, Ron H N van Schaik, Jennifer J Hu, Maureen Sanderson, Rohit Varma, Roberta McKean-Cowdin, Mina Torres, Nicholas Mancuso, Sonja I Berndt, Stephen K Van Den Eeden, Douglas F Easton, Stephen J Chanock, Michael B Cook, Fredrik Wiklund, Hidewaki Nakagawa, John S Witte, Rosalind A Eeles, Zsofia Kote-Jarai, Christopher A Haiman (2021)Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction, In: Nature Genetics53pp. 65-75 Springer Nature
Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
David V Conti, Burcu F Darst, Lilit C Moss, Edward J Saunders, Xin Sheng, Alisha Chou, Fredrick R Schumacher, Ali Amin Al Olama, Sara Benlloch, Tokhir Dadaev, Mark N Brook, Ali Sahimi, Thomas J Hoffmann, Atushi Takahashi, Koichi Matsuda, Yukihide Momozawa, Masashi Fujita, Kenneth Muir, Artitaya Lophatananon, Loic Le Marchand, Peggy Wan, Lynne R Wilkens, Victoria L Stevens, Susan M Gapstur, Brian D Carter, Johanna Schleutker, Teuvo L J Tammela, Csilla Sipeky, Anssi Auvinen, Graham G Giles, Melissa C Southey, Robert J MacInnis, Cezary Cybulski, Dominika Wokołorczyk, Jan Lubiński, David E Neal, Jenny L Donovan, Freddie C Hamdy, Richard M Martin, Børge G Nordestgaard, Sune F Nielsen, Maren Weischer, Stig E Bojesen, Martin Andreas Røder, Peter Iversen, Jyotsna Batra, Suzanne Chambers, Leire Moya, Lisa Horvath, Judith A Clements, Wayne Tilley, Gail P Risbridger, Henrik Gronberg, Markus Aly, Robert Szulkin, Martin Eklund, Tobias Nordström, Nora Pashayan, Alison M Dunning, Maya Ghoussaini, Ruth C Travis, Tim J Key, Elio Riboli, Jong Y Park, Thomas A Sellers, Hui-Yi Lin, Demetrius Albanes, Stephanie J Weinstein, Lorelei A Mucci, Edward Giovannucci, Sara Lindstrom, Peter Kraft, David J Hunter, Kathryn L Penney, Constance Turman, Catherine M Tangen, Phyllis J Goodman, Ian M Thompson, Jr, Robert J Hamilton, Neil E Fleshner, Antonio Finelli, Marie-Élise Parent, Janet L Stanford, Elaine A Ostrander, Milan S Geybels, Stella Koutros, Laura E Beane Freeman, Meir Stampfer, Alicja Wolk, Niclas Håkansson, Gerald L Andriole, Robert N Hoover, Mitchell J Machiela, Karina Dalsgaard Sørensen, Michael Borre, William J Blot, Wei Zheng, Edward D Yeboah, James E Mensah, Yong-Jie Lu, Hong-Wei Zhang, Ninghan Feng, Xueying Mao, Yudong Wu, Shan-Chao Zhao, Zan Sun, Stephen N Thibodeau, Shannon K McDonnell, Daniel J Schaid, Catharine M L West, Neil Burnet, Gill Barnett, Christiane Maier, Thomas Schnoeller, Manuel Luedeke, Adam S Kibel, Bettina F Drake, Olivier Cussenot, Géraldine Cancel-Tassin, Florence Menegaux, Thérèse Truong, Yves Akoli Koudou, Esther M John, Eli Marie Grindedal, Lovise Maehle, Kay-Tee Khaw, Sue A Ingles, Mariana C Stern, Ana Vega, Antonio Gómez-Caamaño, Laura Fachal, Barry S Rosenstein, Sarah L Kerns, Harry Ostrer, Manuel R Teixeira, Paula Paulo, Andreia Brandão, Stephen Watya, Alexander Lubwama, Jeannette T Bensen, Elizabeth T H Fontham, James Mohler, Jack A Taylor, Manolis Kogevinas, Javier Llorca, Gemma Castaño-Vinyals, Lisa Cannon-Albright, Craig C Teerlink, Chad D Huff, Sara S Strom, Luc Multigner, Pascal Blanchet, Laurent Brureau, Radka Kaneva, Chavdar Slavov, Vanio Mitev, Robin J Leach, Brandi Weaver, Hermann Brenner, Katarina Cuk, Bernd Holleczek, Kai-Uwe Saum, Eric A Klein, Ann W Hsing, Rick A Kittles, Adam B Murphy, Christopher J Logothetis, Jeri Kim, Susan L Neuhausen, Linda Steele, Yuan Chun Ding, William B Isaacs, Barbara Nemesure, Anselm J M Hennis, John Carpten, Hardev Pandha, Agnieszka Michael, Kim De Ruyck, Gert De Meerleer, Piet Ost, Jianfeng Xu, Azad Razack, Jasmine Lim, Soo-Hwang Teo, Lisa F Newcomb, Daniel W Lin, Jay H Fowke, Christine Neslund-Dudas, Benjamin A Rybicki, Marija Gamulin, Davor Lessel, Tomislav Kulis, Nawaid Usmani, Sandeep Singhal, Matthew Parliament, Frank Claessens, Steven Joniau, Thomas Van den Broeck, Manuela Gago-Dominguez, Jose Esteban Castelao, Maria Elena Martinez, Samantha Larkin, Paul A Townsend, Claire Aukim-Hastie, William S Bush, Melinda C Aldrich, Dana C Crawford, Shiv Srivastava, Jennifer C Cullen, Gyorgy Petrovics, Graham Casey, Monique J Roobol, Guido Jenster, Ron H N van Schaik, Jennifer J Hu, Maureen Sanderson, Rohit Varma, Roberta McKean-Cowdin, Mina Torres, Nicholas Mancuso, Sonja I Berndt, Stephen K Van Den Eeden, Douglas F Easton, Stephen J Chanock, Michael B Cook, Fredrik Wiklund, Hidewaki Nakagawa, John S Witte, Rosalind A Eeles, Zsofia Kote-Jarai, PAUL ANDREW TOWNSEND, Christopher A Haiman (2021)Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction, In: Nature Genetics53(3)pp. 413-413 Springer Nature
Correction to: Nature Genetics https://doi.org/10.1038/s41588-020-00748-0, published online 4 January 2021.
In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.
EJ Saunders, T Dadaev, DA Leongamornlert, AA Olama, S Benlloch, GG Giles, F Wiklund, H Grönberg, CA Haiman, J Schleutker, BG Nordestgaard, RC Travis, D Neal, N Pasayan, KT Khaw, JL Stanford, WJ Blot, SN Thibodeau, C Maier, AS Kibel, C Cybulski, L Cannon-Albright, H Brenner, JY Park, R Kaneva, J Batra, MR Teixeira, H Pandha, K Govindasami, K Muir, UK Genetic Prostate Cancer Study Collaborators, UK ProtecT Study Collaborators, PRACTICAL Consortium, DF Easton, RA Eeles, Z Kote-Jarai (2016)Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array., In: British Journal of Cancer114pp. 945-952 Cancer Research UK
BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of ∼100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.
C Bonilla, SJ Lewis, RM Martin, JL Donovan, FC Hamdy, DE Neal, R Eeles, D Easton, Z Kote-Jarai, AA Al Olama, S Benlloch, K Muir, GG Giles, F Wiklund, H Gronberg, CA Haiman, J Schleutker, BG Nordestgaard, RC Travis, N Pashayan, KT Khaw, JL Stanford, WJ Blot, S Thibodeau, C Maier, AS Kibel, C Cybulski, L Cannon-Albright, H Brenner, J Park, R Kaneva, J Batra, MR Teixeira, H Pandha, M Lathrop, G Davey Smith, PRACTICAL Consortium (2016)Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort., In: BMC Medicine14(1)pp. 66-76 BioMed Central
Background: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach. Methods: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample. Results: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64–0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43–91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91–1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90–0.98), but not with disease grade. Conclusions: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease.
AE Taylor, RM Martin, Z Kote-Jarai, AA Al Olama, S Benlloch, K Muir, GG Giles, F Wiklund, H Gronberg, CA Haiman, J Schleutker, BG Nordestgaard, RC Travis, D Neal, N Pashayan, KT Khaw, W Blott, S Thibodeau, C Maier, AS Kibel, C Cybulski, L Cannon‐Albright, H Brenner, J Park, R Kaneva, J Batra, MR Teixeira, HS Pandha, . PRACTICAL Consortium, J Donovan, MR Munafo (2016)Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis, In: International Journal of Cancer
Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all-cause and prostate cancer-specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high-grade compared to low-grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all-cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer-specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression.
C Bonilla, SJ Lewis, M Rowlands, TR Gaunt, G Davey Smith, D Gunnell, T Palmer, JL Donovan, FC Hamdy, DE Neal, R Eeles, D Easton, Z Kote-Jarai, AA Al Olama, S Benlloch, K Muir, GG Giles, F Wiklund, H Gronberg, CA Haiman, J Schleutker, BG Nordestgaard, RC Travis, N Pashayan, K Khaw, JL Stanford, WJ Blot, S Thibodeau, C Maier, AS Kibel, C Cybulski, L Cannon-Albright, H Brenner, J Park, R Kaneva, J Batra, MR Teixeira, HS Pandha, M PRACTICAL consortium, M Lathrop, RM Martin, JMP Holly (2016)Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: genetic variants as instruments for circulating levels, In: International Journal of Cancer139(7)pp. 1520-1533
Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.
C Brunner, NM Davies, RM Martin, R Eeles, D Easton, Z Kote-Jarai, AA Al Olama, S Benlloch, K Muir, G Giles, F Wiklund, H Gronberg, CA Haiman, J Schleutker, BG Nordestgaard, RC Travis, D Neal, J Donovan, FC Hamdy, N Pashayan, KT Khaw, JL Stanford, WJ Blot, S Thibodeau, C Maier, AS Kibel, C Cybulski, L Cannon-Albright, H Brenner, J Park, R Kaneva, J Batra, MR Teixeira, HS Pandha, L PRACTICAL Consortium, L Zuccolo (2016)Alcohol Consumption and Prostate Cancer Incidence and Progression: a Mendelian Randomization Study, In: International Journal of Cancer
Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In the current study we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival.
SET Larkin, HE Johnston, TR Jackson, DG Jamieson, TI Roumeliotis, CI Mockridge, A Manousopoulou, EK Papachristou, MD Brown, NW Clarke, HS Pandha, CL Aukim-Hastie, MS Cragg, SD Garbis, PA Townsend (2016)Detection of candidate biomarkers of prostate cancer progression in serum: a depletion-free 3D LC/MS quantitative proteomics pilot study, In: British Journal of Cancer Springer Nature
Background: Prostate cancer (PCa) is the most common male cancer in the United Kingdom and we aimed to identify clinically relevant biomarkers corresponding to stage progression of the disease. Methods: We used enhanced proteomic profiling of PCa progression using iTRAQ 3D LC mass spectrometry on high-quality serum samples to identify biomarkers of PCa. Results: We identified >1000 proteins. Following specific inclusion/exclusion criteria we targeted seven proteins of which two were validated by ELISA and six potentially interacted forming an ‘interactome’ with only a single protein linking each marker. This network also includes accepted cancer markers, such as TNF, STAT3, NF-κB and IL6. Conclusions: Our linked and interrelated biomarker network highlights the potential utility of six of our seven markers as a panel for diagnosing PCa and, critically, in determining the stage of the disease. Our validation analysis of the MS-identified proteins found that SAA alongside KLK3 may improve categorisation of PCa than by KLK3 alone, and that TSR1, although not significant in this model, might also be a clinically relevant biomarker.
Tim Kottke, Laura Evgin, Kevin G. Shim, Diana Rommelfanger, Nicolas Boisgerault, Shane Zaidi, Rosa Maria Diaz, Jill Thompson, Elizabeth Ilett, Matt Coffey, Peter Selby, Hardev Pandha, Kevin Harrington, Alan Melcher, Richard Vile (2017)Subversion of NK-cell and TNFα Immune Surveillance Drives Tumor Recurrence, In: Cancer Immunology Research5(11)pp. 1029-1045 American Association for Cancer Research
Understanding how incompletely cleared primary tumors transition from minimal residual disease (MRD) into treatment resistant, immune-invisible recurrences has major clinical significance. We show here that this transition is mediated through the subversion of two key elements of innate immune surveillance. In the first, the role of TNFalpha changes from an antitumor effector against primary tumors into a growth promoter for MRD. Second, whereas primary tumors induced a natural killer (NK)-mediated cytokine response characterized by low IL6 and elevated IFNgamma, PD-L1hi MRD cells promoted the secretion of IL6 but minimal IFNgamma, inhibiting both NK cell and T-cell surveillance. Tumor recurrence was promoted by trauma- or infection-like stimuli inducing VEGF and TNFalpha which stimulated the growth of MRD tumors. Finally, therapies which blocked PD1, TNFalpha or NK cells delayed or prevented recurrence. These data show how innate immune surveillance mechanisms, which control infection and growth of primary tumors, are exploited by recurrent, competent tumors and identifies therapeutic targets in patients with MRD known to be at high risk of relapse.
A Horvath, GR Simpson, RS Coffin, H Mostafid, H Pandha (2010)NOVEL INTRAVESICAL THERAPY FOR NON MUSCLE INVASIVE BLADDER CANCER USING A GENETICALLY MODIFIED ONCOLYTIC HERPES SIMPLEX VIRUS, In: EUR UROL SUPPL9(6)pp. 646-646
AA Al Olama, T Dadaev, DJ Hazelett, Q Li, D Leongamornlert, EJ Saunders, S Stephens, C Cieza-Borrella, I Whitmore, SB Garcia, GG Giles, MC Southey, L Fitzgerald, H Gronberg, F Wiklund, M Aly, BE Henderson, F Schumacher, CA Haiman, J Schleutker, T Wahlfors, TL Tammela, BG Nordestgaard, TJ Key, RC Travis, DE Neal, JL Donovan, FC Hamdy, P Pharoah, N Pashayan, K-T Khaw, JL Stanford, SN Thibodeau, SK Mcdonnell, DJ Schaid, C Maier, W Vogel, M Luedeke, K Herkommer, AS Kibel, C Cybulski, D Wokolorczyk, W Kluzniak, L Cannon-Albright, H Brenner, K Butterbach, V Arndt, JY Park, T Sellers, H-Y Lin, C Slavov, R Kaneva, V Mitev, J Batra, JA Clements, A Spurdle, MR Teixeira, P Paulo, S Maia, H Pandha, A Michael, A Kierzek, K Govindasami, M Guy, A Lophatonanon, K Muir, A Vinuela, AA Brown, M Freedman, DV Conti, D Easton, GA Coetzee, RA Eeles, Z Kote-Jarai (2015)Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans, In: HUMAN MOLECULAR GENETICS24(19)pp. 5589-5602 OXFORD UNIV PRESS
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region
TR Daniels, II Neacato, JA Rodriguez, HS Pandha, R Morgan, ML Penichet (2010)Disruption of HOX activity leads to cell death that can be enhanced by the interference of iron uptake in malignant B cells, In: LEUKEMIA24(9)pp. 1555-1565 NATURE PUBLISHING GROUP
L Heinemann, GR Simpson, NE Annels, R Vile, A Melcher, R Prestwich, KJ Harrington, HS Pandha (2010)The Effect of Cell Cycle Synchronization on Tumor Sensitivity to Reovirus Oncolysis, In: MOLECULAR THERAPY18(12)pp. 2085-2093 NATURE PUBLISHING GROUP
D Enting, ML Iannitto, H Pandha, S Chowdhury, A Hayday (2015)Effects of Concomitant Therapies on gamma delta T Cell Responses to Zoledronate in Patients with Advanced Prostate Cancer, In: CLINICAL ONCOLOGY27(3)pp. E4-E4 ELSEVIER SCIENCE LONDON
SJ Crabb, J Douglas, NE Annels, R Morgan, G Packham, HS Pandha (2014)Engrailed-2 (EN2) protein expression and prognosis in bladder cancer following radical cystectomy (RC)., In: JOURNAL OF CLINICAL ONCOLOGY32(15)
ES Appleton, S Turnbull, C Ralph, E West, K Scott, K Harrington, H Pandha, A Melcher (2015)Talimogene laherparepvec in the treatment of melanoma, In: EXPERT OPINION ON BIOLOGICAL THERAPY15(10)pp. 1517-1530 TAYLOR & FRANCIS LTD
OG Donnelly, F Errington-Mais, R Prestwich, K Harrington, H Pandha, R Vile, AA Melcher (2011)Recent Clinical Experience With Oncolytic Viruses., In: Curr Pharm Biotechnol
There has been interest in using viruses to treat cancer for over a century. Recent clinical efforts, driven on by significant preclinical advances, have focussed on the safety of using replication-competent viruses. Recently published clinical trials of six oncolytic viruses (adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia) have added to the accumulating data that endorse oncolytic viruses as a safe and well tolerated treatment approach. Conclusive evidence of efficacy remains to be demonstrated, but randomised clinical trials are now underway.
GR Simpson, M Ajaz, FA Launchbury, G Bolton, AA Melcher, KJ Harrington, GG Au, DR Shafren, HS Pandha (2014)Major synergy between Coxsackievirus A21 (CAVATAK (TM)) and radiotherapy or chemotherapy in bladder cancer, In: HUMAN GENE THERAPY25(12)pp. A13-A13
SP Kar, J Beesley, AA Al Olama, K Michailidou, J Tyrer, ZA Kote-Jarai, K Lawrenson, S Lindstrom, SJ Ramus, DJ Thompson, AS Kibel, A Dansonka-Mieszkowska, A Michael, AK Dieffenbach, A Gentry-Maharaj, AS Whittemore, A Wolk, A Monteiro, A Peixoto, A Kierzek, A Cox, A Rudolph, A Gonzalez-Neira, AH Wu, A Lindblom, A Swerdlow, A Ziogas, AB Ekici, B Burwinkel, BY Karlan, BG Nordestgaard, C Blomqvist, C Phelan, C McLean, CL Pearce, C Vachon, C Cybulski, C Slavov, C Stegmaier, C Maier, CB Ambrosone, CK Hogdall, CC Teerlink, D Kang, DC Tessier, DJ Schaid, DO Stram, DW Cramer, DE Neal, D Eccles, D Flesch-Janys, DRV Edwards, D Wokozorczyk, DA Levine, D Yannoukakos, EJ Sawyer, EV Bandera, EM Poole, EL Goode, E Khusnutdinova, E Hogdall, F Song, F Bruinsma, F Heitz, F Modugno, FC Hamdy, F Wiklund, GG Giles, H Olsson, H Wildiers, H-U Ulmer, H Pandha, HA Risch, H Darabi, HB Salvesen, H Nevanlinna, H Gronberg, H Brenner, H Brauch, H Anton-Culver, H Song, H-Y Lim, I McNeish, I Campbell, I Vergote, J Gronwald, J Lubinski, JL Stanford, J Bentez, JA Doherty, JB Permuth, J Chang-Claude, JL Donovan, J Dennis, JM Schildkraut, J Schleutker, JL Hopper, J Kupryjanczyk, JY Park, J Figueroa, JA Clements, JA Knight, J Peto, JM Cunningham, J Pow-Sang, J Batra, K Czene, KH Lu, K Herkommer, K-T Khaw, K Matsuo, K Muir, K Offitt, K Chen, KB Moysich, K Aittomaki, K Odunsi, LA Kiemeney, LFAG Massuger, LM Fitzgerald, LS Cook, L Cannon-Albright, MJ Hooning, MC Pike, MK Bolla, M Luedeke, MR Teixeira, MT Goodman, MK Schmidt, M Riggan, M Aly, MA Rossing, MW Beckmann, M Moisse, M Sanderson, MC Southey, M Jones, M Lush, MAT Hildebrandt, M-F Hou, MJ Schoemaker, M Garcia-Closas, N Bogdanova, N Rahman, ND Le, N Orr, N Wentzensen, N Pashayan, P Peterlongo, P Guenel, P Brennan, P Paulo, PM Webb, P Broberg, PA Fasching, P Devilee, Q Wang, Q Cai, Q Li, R Kaneva, R Butzow, RK Kopperud, RK Schmutzler, RA Stephenson, RJ MacInnis, RN Hoover, R Winqvist, R Ness, RL Milne, RC Travis, S Benlloch, SH Olson, SK McDonnell, SS Tworoger, SA Maia, S Berndt, SC Lee, S-H Teo, SN Thibodeau, SE Bojesen, SM Gapstur, SK Kjaer, T Pejovic, TLJ Tammela, T Doerk, T Bruening, T Wahlfors, TJ Key, TL Edwards, U Menon, U Hamann, V Mitev, V-M Kosma, VW Setiawan, V Kristensen, V Arndt, W Vogel, W Zheng, W Sieh, WJ Blot, W Kluzniak, X-O Shu, Y-T Gao, F Schumacher, ML Freedman, A Berchuck, AM Dunning, J Simard, CA Haiman, A Spurdle, TA Sellers, DJ Hunter, BE Henderson, P Kraft, SJ Chanock, FJ Couch, P Hall, SA Gayther, DF Easton, G Chenevix-Trench, R Eeles, PDP Pharoah, D Lambrechts (2016)Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types, In: CANCER DISCOVERY6(9)pp. 1052-1067 AMER ASSOC CANCER RESEARCH
Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10-8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10-5 in the three-cancer meta-analysis.
M De Paoli, P Perco, I Muehlberger, A Lukas, H Pandha, R Morgan, GJ Feng, C Marquette (2015)Disease map-based biomarker selection and pre-validation for bladder cancer diagnostic, In: BIOMARKERS20(5)pp. 328-337 TAYLOR & FRANCIS LTD
RA Alharbi, R Pettengell, HS Pandha, R Morgan (2012)The role of HOX genes in normal hematopoiesis and acute leukemia., In: Leukemia Nature Publishing Group
The HOX genes are a highly conserved family of homeodomain-containing transcription factors that specify cell identity in early development and, subsequently, in a number of adult processes including hematopoiesis. The dysregulation of HOX genes is associated with a number of malignancies including acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), where they have been shown to support the immortalization of leukemic cells both as chimeric partners in fusion genes and when overexpressed in their wild type form. This review covers our current understanding of the role of HOX genes in normal hematopoiesis, AML and ALL, with particular emphasis on the similarities and differences of HOX function in these contexts, their hematopoietic downstream genes targets and implications for therapy.Leukemia accepted article preview online, 5 December 2012; doi:10.1038/leu.2012.356.
K Twigger, V Roulstone, J Kyula, EM Karapanagiotou, KN Syrigos, R Morgan, C White, S Bhide, G Nuovo, M Coffey, B Thompson, A Jebar, F Errington, AA Melcher, RG Vile, HS Pandha, KJ Harrington (2012)Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway., In: BMC Cancer12pp. 368-?
Reovirus exploits aberrant signalling downstream of Ras to mediate tumor-specific oncolysis. Since ~90% squamous cell carcinomas of the head and neck (SCCHN) over-express EGFR and SCCHN cell lines are sensitive to oncolytic reovirus, we conducted a detailed analysis of the effects of reovirus in 15 head and neck cancer cell lines. Both pre- and post-entry events were studied in an attempt to define biomarkers predictive of sensitivity/resistance to reovirus. In particular, we analysed the role of EGFR/Ras signalling in determining virus-mediated cytotoxicity in SCCHN.
Poulam M. Patel, Christian H. Ottensmeier, Clive Mulatero, Paul Lorigan, Ruth Plummer, Hardev Pandha, Somaia Elsheikh, Efthymios Hadjimichael, Naty Villasanti, Sally E. Adams, Michelle Cunnell, Rachael L. Metheringham, Victoria A. Brentville, Lee Machado, Ian Daniels, Mohamed Gijon, Drew Hannaman, Lindy G. Durrant (2018)Targeting gp100 and TRP-2 with a DNA vaccine: Incorporating T cell epitopes with a human IgG1 antibody induces potent T cell responses that are associated with favourable clinical outcome in a phase I/II trial, In: OncoImmunology7(6)e1433516pp. e1433516-1 Taylor & Francis
A DNA vaccine, SCIB1, incorporating two CD8 and two CD4 epitopes from TRP-2/gp100 was evaluated in patients with metastatic melanoma. Each patient received SCIB1 via intramuscular injection with electroporation. The trial was designed to find the safest dose of SCIB1 which induced immune/clinical responses in patients with or without tumour. Fifteen patients with tumor received SCIB1 doses of 0.4-8 mg whilst 20 fully-resected patients received 2–8 mg doses. Twelve patients elected to continue immunization every 3 months for up to 39 months. SCIB1 induced dose-dependent T cell responses in 88% of patients with no serious adverse effects or dose limiting toxicities. The intensity of the T cell responses was significantly higher in patients receiving 4 mg doses without tumor when compared to those with tumor (p ˂ 0.01). In contrast, patients with tumor showed a significantly higher response to the 8 mg dose than the 4 mg dose (p ˂ 0.03) but there was no significant difference in the patients without tumor. One of 15 patients with measurable disease showed an objective tumor response and 7/15 showed stable disease. 5/20 fully-resected patients have experienced disease recurrence but all remained alive at the cut-off date with a median observation time of 37 months. A positive clinical outcome was associated with MHC-I and MHC-II expression on tumors prior to therapy (p = 0.027).
We conclude that SCIB1 is well tolerated and stimulates potent T cell responses in melanoma patients. It deserves further evaluation as a single agent adjuvant therapy or in combination with checkpoint inhibitors in advanced disease.
GC Bolton, GR Simpson, M Coffey, K Harrington, R Morgan, N Annels, FA Launchbury, M Ajaz, H Pandha (2014)Resistance to Oncolytic Reovirus is associated with high expression of Yes-Associated Protein-1 (YAP-1) in Head and Neck Cancer, In: HUMAN GENE THERAPY25(12)pp. A12-A13
ME Gore, CM Nutting, HS Pandha, AA Melcher, RG Vile, KJ Harrington (2008)T-cell responses to survivin in cancer patients undergoing radiation therapy, In: Clinical Cancer Research14(15)pp. 4883-4883
GW Middleton, NE Annels, HS Pandha (2012)Are we ready to start studies of Th17 cell manipulation as a therapy for cancer?, In: Cancer Immunol Immunother61(1)pp. 1-7
From a therapeutic perspective, the bourgeoning literature on Th17 cells should allow us to decide whether to rationally pursue the manipulation of Th17 cells in cancer. The purpose of this review is to attempt a synthesis of a number of contradictory conclusions as to the role that these cells are playing in the process of tumourigenesis in order to provide guidance as to whether our current understanding is sufficient to safely pursue Th17-targeted therapy in cancer at this time. Th17 cells are a highly plastic population and the cytokine drivers for Th17 cell generation and skewing will vary between various cancers and importantly between different sites of tumour involvement in any individual patient. The net impact of the pro-angiogenic IL-17 produced not only by Th17 cells but by other cells particularly macrophages and the anti-tumour effects of Th1/Th17 cells will in turn be determined by the complex interplay of diverse chemokines and cytokines in any tumour microenvironment. Th17 cells that fail to home to tumours may be immunosuppressive. The complexity of IL-17 and Th17 dynamics makes easy prediction of the effects of either enhancing or suppressing Th17 cell differentiation in cancer problematic.
E Ilett, T Kottke, O Donnelly, J Thompson, C Willmon, R Diaz, S Zaidi, M Coffey, P Selby, K Harrington, H Pandha, A Melcher, R Vile (2014)Direct, Cytokine-Conditioned, In Vivo Cell Loading for Systemic Delivery of Oncolytic Viruses, In: MOLECULAR THERAPY22pp. S245-S245
C Comins, Guy Simpson, William Rogers, Kate Relph, K Harrington, A Melcher, V Roulestone, J Kyula, Hardev Pandha (2018)Synergistic anti-tumour effects of rapamycin and oncolytic reovirus, In: Cancer Gene Therapy25pp. 148-160 Nature Publishing Group
There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent,Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anti-cancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an anti-reovirus neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin, However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic anti-tumour efficacy of reovirus and rapamycin combination.
T Kottke, O Donnelly, N Boisgerault, R Diaz, D Rommelfanger-Konkol, J Pulido, J Thompson, D Mukhopadhyay, K Knutson, M Behrens, R Kaspar, M Coffey, P Selby, K Harrington, A Melcher, H Pandha, R Vile (2013)Tumor Relapse Is Associated with an Innate Immune Resistant Phenotype across Tumor and Treatment Types Which Can Be Targeted with Rational Second Line Therapies, In: MOLECULAR THERAPY21pp. S249-S249
B Meyer, M Denyer, R Morgan, H Pandha (2007)Cellular effects of phosphoramide mustard, the active metabolite of cyclophosphamide, on naturally-occuring human CD4(+) CD25(+) regulatory T cells, In: JOURNAL OF IMMUNOTHERAPY30(8)pp. 887-887
SE McGrath, A Michael, H Pandha, R Morgan (2013)Engrailed homeobox transcription factors as potential markers and targets in cancer., In: FEBS Lett587(6)pp. 549-554
Engrailed (En) is a member of the homeobox gene family, which encodes a homeodomain-containing transcription factor that is essential during early development. The only known site of normal adult Engrailed protein (EN) expression is in the nervous system, and it has been implicated in the development of both young-onset Parkinson's disease as well as autism. Over-expression of EN has been linked to tumour development in adults, particularly in breast, prostate, melanoma and ovarian cancers, and there is a growing interest in its role as a diagnostic and prognostic biomarker. It is hoped that further work may confirm associations between En expression and therapy-resistant, poor prognosis cancers, similar to that identified with other homeobox gene profiles.
M Blanchard, KG Shim, MP Grams, K Rajani, RM Diaz, KM Furutani, J Thompson, KR Olivier, SS Park, SN Markovic, H Pandha, A Melcher, K Harrington, S Zaidi, R Vile (2015)Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy, In: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS93(3)pp. 577-587 ELSEVIER SCIENCE INC
NE Annels, GR Simpson, S Bokaee, C Riley, M Denyer, H Pandha, R Morgan (2012)Modulation of Regulatory T Cells by Targeting The NFAT-FOXP3 Protein: Protein Interaction, In: JOURNAL OF IMMUNOTHERAPY35(9)pp. 775-775
S Javed, R Morgan, R Hindley, S Bott, C Eden, H Pandha, S Langley (2014)Urinary engrailed-2 levels in healthy volunteers, patients on active surveillance and following radical prostate cancer treatment, In: BJU INTERNATIONAL113pp. 43-44
L Heinemann, T Kottke, R Vile, MC Coffey, K Harrington, A Melcher, HS Pandha (2008)Synergistic Anti-Tumor Activity of Oncolytic Reovirus and Docetaxel in a PC-3 Prostate Cancer Mouse Model, In: JOURNAL OF IMMUNOTHERAPY31(9)pp. 951-952
T Kottke, O Donnelly, E Ilett, J Thompson, R Diaz, M Coffey, P Selby, H Pandha, K Harrington, A Melcher, R Vile (2013)In Vivo Expansion of a Recipient Population of Cell Carriers Allows for Highly Effective Systemic Delivery of Oncolytic Reovirus Even in the Presence of Neutralizing Antibody, In: MOLECULAR THERAPY21pp. S7-S7
SM Walker, LA Knight, AM McCavigan, GE Logan, V Berge, A Sherif, Hardev Pandha, AY Warren, C Davidson, A Uprichard, JK Blayney, B Price, GL Jellema, A Svindland, SS McDade, CG Eden, C Foster, IG Mills, DE Neal, MD Mason, EW Kay, DJ Waugh, DP Harkin, RW Watson, NW Clarke, RD Kennedy (2017)Molecular Subgroup of Primary Prostate Cancer Presenting with Metastatic Biology, In: European Urology72(4)pp. 509-518 Elsevier
BACKGROUND: Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy. OBJECTIVE: To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy. DESIGN, SETTING & PARTICIPANTS: Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months. OUTCOME MEASURES & STATISTICAL ANALYSIS: Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analyzed using multivariable Cox regression and log-rank analysis. RESULTS & LIMITATIONS: A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (Metastatic Assay) was developed and independently validated in the radical prostatectomy samples. Metastatic Assay positive patients had increased risk of biochemical recurrence (Multivariable HR 1.62 [1.13-2.33]; p= 0.0092) and metastatic recurrence (Multivariable HR=3.20 (1.76-5.80); p=0.0001). A combined model with CAPRA-S identified patients at increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; p<0.0001 and HR=7.53 [4.13-13.73]; p<0.0001 respectively. The retrospective nature of the study is acknowledged as a potential limitation. CONCLUSIONS: The Metastatic Assay may identify a molecular subgroup of primary prostate cancers with metastatic potential. PATIENT SUMMARY: The Metastatic Assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher risk population.
H Pandha, C D'Ambrosio, S Heenan, N Hyde, S Di Palma, C Nutting, K Relph, K Harrington (2009)Indium-labelled Autologous Dendritic Cells Migrate to Local Lymph Nodes after Intratumoural Injection in Head and Neck Cancer Patients, In: CLINICAL ONCOLOGY21(4)pp. 363-364 ELSEVIER SCIENCE LONDON
NE Annels, H Pandha (2013)Immunotherapy, In: Prostate Cancer: A Comprehensive Perspectivepp. 925-934
© 2013 Springer-Verlag London. All rights are reserved.The approval in April 2010 by the FDA in the USA of a prostate cancer vaccine (Sipuleucel-T, Provenge, Dendreon Inc.) may herald a new era in T-cell-directed cancer therapies. The magnitude of scientific effort to reach this point should not be underestimated. The key has been unraveling the complex mechanisms between the recognition of tumor antigen, breaking immune tolerance, and generation of a long-lasting and clinically meaningful cellular response. Therapeutic vaccines (i.e., vaccines for patients with ongoing disease) have two objectives: priming Ag-specific T cells and reprogramming memory T cells (i.e., a transformation from one type of immunity to another, for example, regulatory to cytotoxic). Numerous therapeutic approaches have been tested in prostate cancer patients, including autologous and allogeneic tumor cells modified to express various cytokines, peptides, proteins, and DNA vaccines. The evolution of cellular vaccines includes addressing the local immunosuppressive tumor microenvironment, modulating immune response through checkpoint blockade and, importantly, combining cellular immunotherapy with other treatment modalities such as chemotherapy exploiting their intrinsic immunomodulatory properties.
VA Jennings, EJ Ilett, KJ Scott, EJ West, R Vile, H Pandha, K Harrington, A Young, GD Hall, M Coffey, P Selby, F Errington-Mais, AA Melcher (2014)Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites, In: INTERNATIONAL JOURNAL OF CANCER134(5)pp. 1091-1101 WILEY-BLACKWELL
CS Verbeke, S Hamdan, J Booth, HS Pandha, GE Blair (2006)Limited expression of the Coxsackie and Adenovirus Receptor in pancreatic cancer may reduce suitability of adenoviral gene therapy, In: JOURNAL OF PATHOLOGY210pp. 2-2
A-M Anesti, GR Simpson, T Price, HS Pandha, RS Coffin (2010)Expression of RNA interference triggers from an oncolytic herpes simplex virus results in specific silencing in tumour cells in vitro and tumours in vivo, In: BMC CANCER10ARTN 4pp. ?-? BIOMED CENTRAL LTD
D Enting, ML Iannitto, E Binda, M Eberl, H Pandha, A Hayday (2013)Effects of concomitant therapies on gd T cell responses to zoledronate in patients with advanced prostate cancer, In: IMMUNOLOGY140pp. 69-69
M Ismail, R Morgan, K Harrington, J Davies, H Pandha (2009)Enhancing prostate cancer cryotherapy using tumour necrosis factor related apoptosis-inducing ligand (TRAIL) sensitisation in an in vitro cryotherapy model, In: CRYOBIOLOGY59(2)pp. 207-213 ACADEMIC PRESS INC ELSEVIER SCIENCE
N Boisgerault, T Kottke, J Pulido, J Thompson, RM Diaz, D Rommelfanger-Konkol, A Embry, D Saenz, E Poeschla, H Pandha, K Harrington, A Melcher, P Selby, R Vile (2013)Functional Cloning of Recurrence-specific Antigens Identifies Molecular Targets to Treat Tumor Relapse, In: MOLECULAR THERAPY21(8)pp. 1507-1516 NATURE PUBLISHING GROUP
N Boisgerault, J Pulido, T Kottke, O Donnelly, E Celis, J Thompson, R Diaz, K Harrington, H Pandha, P Selby, A Melcher, R Vile (2013)Tumor Recurrences Share Immunogenic Antigens across Both Tumor Types and Primary Treatments Which Can Be Therapeutically Targeted with VSV-cDNA Libraries, In: MOLECULAR THERAPY21pp. S152-S152
E Killick, R Morgan, F Launchbury, E Bancroft, E Page, E Castro, Z Kote-Jarai, A Aprikian, I Blanco, V Clowes, S Domchek, F Douglas, D Eccles, DG Evans, M Harris, J Kirk, J Lam, G Lindeman, G Mitchell, N Pachter, C Selkirk, K Tucker, J Zgajnar, R Eeles, H Pandha (2013)Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men., In: Sci Rep3pp. 2059-?
Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals.
M Ismail, R Morgan, J Davies, H Pandha (2008)Immunoregulatory effects of cryo-treated prostate cancer cells on human dendritic cells using a novel in vitro cryotherapy model, In: JOURNAL OF UROLOGY179(4)pp. 48-48
MC Errico, F Felicetti, L Bottero, G Mattia, A Boe, N Felli, M Petrini, M Bellenghi, HS Pandha, M Calvaruso, C Tripodo, MP Colombo, R Morgan, A Care (2013)The abrogation of the HOXB7/PBX2 complex induces apoptosis in melanoma through the miR-221&222-c-FOS pathway, In: INTERNATIONAL JOURNAL OF CANCER133(4)pp. 879-892 WILEY-BLACKWELL
NM Davies, TR Gaunt, SJ Lewis, J Holly, JL Donovan, FC Hamdy, JP Kemp, R Eeles, D Easton, Z Kote-Jarai, AA Al Olama, S Benlloch, K Muir, GG Giles, F Wiklund, H Gronberg, CA Haiman, J Schleutker, BG Nordestgaard, RC Travis, D Neal, N Pashayan, K-T Khaw, JL Stanford, WJ Blot, S Thibodeau, C Maier, AS Kibel, C Cybulski, L Cannon-Albright, H Brenner, J Park, R Kaneva, J Batra, MR Teixeira, H Pandha, M Lathrop, GD Smith, RM Martin (2015)The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium, In: CANCER CAUSES & CONTROL26(11)pp. 1603-1616 SPRINGER
A Ravaud, RJ Motzer, H Pandha, M Staehler, DJ George, A Pantuck, A Patel, P Gerletti, L Chen, J Patard (2012)SUNITINIB TREATMENT OF RENAL ADJUVANT CANCER (S-TRAC): A RANDOMIZED, DOUBLE-BLIND, PHASE III STUDY OF SUNITINIB VS. PLACEBO IN SUBJECTS AT HIGH RISK OF RECURRENT RENAL CELL CARCINOMA (RCC), In: ANNALS OF ONCOLOGY23pp. 292-293
A Michael, C Riley, S Bokaee, M Denyer, HS Pandha, NE Annels (2011)EN2: A candidate antigen for the development of targeted therapies in ovarian cancer., In: JOURNAL OF CLINICAL ONCOLOGY29(15) AMER SOC CLINICAL ONCOLOGY
L Shears, L Plowright, K Harrington, HS Pandha, R Morgan (2008)Disrupting the Interaction Between HOX and PBX Causes Necrotic and Apoptotic Cell Death in the Renal Cancer Lines CaKi-2 and 769-P, In: J UROLOGY180(5)pp. 2196-2201 ELSEVIER SCIENCE INC
A Michael, S McGrath, N Annels, M Denyer, R Morgan, H Pandha (2015)Engrailed 2 protein (EN2) as a novel biomarker in epithelial ovarian cancer, In: EUROPEAN JOURNAL OF CANCER51pp. S91-S91
T Kottke, O Donnelly, N Boisgerault, R Diaz, J Thompson, J Chester, H Pandha, K Harrington, A Melcher, R Vile (2012)Characterization of the Mechanisms of Tumor Dormancy and Recurrence Following Front Line Immuno-, Viro- or Suicide Gene-, Therapy, In: MOLECULAR THERAPY20pp. S268-S268
NE Annels, C Riley, S Bokaee, M Denyer, GR Simpson, H Pandha (2010)EN2: A Novel Immunotherapeutic Target for Melanoma, In: J IMMUNOTHER33(8)pp. 891-891
Z Kelly, H Pandha, R Morgan, A Michael (2012)HXR9 AND PARP INHIBITION -A NOVEL THERAPEUTIC IN OVARIAN CANCER, In: ANNALS OF ONCOLOGY23pp. 325-325
R Lord, S Nair, A Schache, J Spicer, N Somaihah, V Khoo, H Pandha (2007)Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: A phase II study, In: JOURNAL OF UROLOGY177(6)pp. 2136-2140 ELSEVIER SCIENCE INC
O Donnelly, K Harrington, A Melcher, H Pandha (2013)Live viruses to treat cancer, In: JOURNAL OF THE ROYAL SOCIETY OF MEDICINE106(8)pp. 310-314 ROYAL SOC MEDICINE PRESS LTD
L Heinemann, G Simpson, K Harrington, A Melcher, MC Coffey, HS Pandha (2008)Synergistic anti-tumour activity of oncolytic Reovirus and cisplatin in a B16.F10 mouse melanoma model, In: EJC SUPPLEMENTS6(12)pp. 99-99
RF Gabitass, NE Annels, J Crawshaw, HS Pandha, GW Middleton (2011)Use of gemcitabine- (Gem) and fluropyrimidine (FP)-based chemotherapy to reduce myeloid-derived suppressor cells (MDSCs) in pancreatic (PC) and esophagogastric cancer (EGC)., In: JOURNAL OF CLINICAL ONCOLOGY29(15) AMER SOC CLINICAL ONCOLOGY
J Pulido, T Kottke, J Thompson, F Galivo, P Wongthida, RM Diaz, D Rommelfanger, E Ilett, L Pease, H Pandha, K Harrington, P Selby, A Melcher, R Vile (2012)Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma, In: Nature Biotechnology30(4)pp. 337-343
Multiple intravenous injections of a cDNA library, derived from human melanoma cell lines and expressed using the highly immunogenic vector vesicular stomatitis virus (VSV), cured mice with established melanoma tumors. Successful tumor eradication was associated with the ability of mouse lymphoid cells to mount a tumor-specific CD4 + interleukin (IL)-17 recall response in vitro. We used this characteristic IL-17 response to screen the VSV-cDNA library and identified three different VSV-cDNA virus clones that, when used in combination but not alone, achieved the same efficacy against tumors as the complete parental virus library. VSV-expressed cDNA libraries can therefore be used to identify tumor rejection antigens that can cooperate to induce anti-tumor responses. This technology should be applicable to antigen discovery for other cancers, as well as for other diseases in which immune reactivity against more than one target antigen contributes to disease pathology. © 2012 Nature America, Inc. All rights reserved.
KL Relph, H Pandha, GR Simpson, A Melcher, K Harrington (2016)Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances, In: Oncolytic Virotherapy2016(5)pp. 1-13 Dove Medical Press
Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena.
L Vidal, K Twigger, C White, M Coffey, B Thompson, J De-Bono, HS Pandha, A Melcher, S Kaye, KJ Harrington (2005)Reovirus enhances radiation cytotoxicity in vitro and in vivo., In: CLINICAL CANCER RESEARCH11(24)pp. 9005S-9006S
NK Khankari, HJ Murff, C Zeng, W Wen, RA Eeles, DF Easton, Z Kote-Jarai, AA Al Olama, S Benlloch, K Muir, GG Giles, F Wiklund, H Gronberg, CA Haiman, J Schleutker, BG Nordestgaard, RC Travis, JL Donovan, N Pashayan, K Khaw, JL Stanford, WJ Blot, SN Thibodeau, C Maier, AS Kibel, C Cybulski, L Cannon-Albright, H Brenner, J Park, R Kaneva, J Batra, MR Teixeira, HS Pandha, W Zheng (2016)Polyunsaturated fatty acids and prostate cancer risk: a Mendelian randomization analysis from the PRACTICAL consortium, In: British Journal of Cancer Springer Nature
Background: Prostate cancer is a common cancer worldwide with no established modifiable lifestyle factors to guide prevention. The associations between polyunsaturated fatty acids (PUFAs) and prostate cancer risk have been inconsistent. Using Mendelian randomisation, we evaluated associations between PUFAs and prostate cancer risk. Methods: We used individual-level data from a consortium of 22 721 cases and 23 034 controls of European ancestry. Externally-weighted PUFA-specific polygenic risk scores (wPRSs), with explanatory variation ranging from 0.65 to 33.07%, were constructed and used to evaluate associations with prostate cancer risk per one standard deviation (s.d.) increase in genetically-predicted plasma PUFA levels using multivariable-adjusted unconditional logistic regression. Results: No overall association was observed between the genetically-predicted PUFAs evaluated in this study and prostate cancer risk. However, risk reductions were observed for short-chain PUFAs, linoleic (ORLA=0.95, 95%CI=0.92, 0.98) and α-linolenic acids (ORALA=0.96, 95%CI=0.93, 0.98), among men <62 years; whereas increased risk was found among men greater than or equal to62 years for LA (ORLA=1.04, 95%CI=1.01, 1.07). For long-chain PUFAs (i.e., arachidonic, eicosapentaenoic, and docosapentaenoic acids), increased risks were observed among men <62 years (ORAA=1.05, 95%CI=1.02, 1.08; OREPA=1.04, 95%CI=1.01, 1.06; ORDPA=1.05, 95%CI=1.02, 1.08). Conclusion: Results from this study suggest that circulating ω-3 and ω-6 PUFAs may have a different role in the aetiology of early- and late-onset prostate cancer.
H Pandha, A Rigg, J John, N Lemoine (2007)Loss of expression of antigen-presenting molecules in human pancreatic cancer and pancreatic cancer cell lines, In: CLINICAL AND EXPERIMENTAL IMMUNOLOGY148(1)pp. 127-135 BLACKWELL PUBLISHING
A Michael, J John, B Meyer, H Pandha (2010)Activation and Genetic Modification of Human Monocyte-Derived Dendritic Cells using Attenuated Salmonella typhimurium, In: THESCIENTIFICWORLDJOURNAL10pp. 393-401 THESCIENTIFICWORLD LTD
L Vidal, H Pandha, K Harrington, P Fong, H Shaw, M Barrett, D Leader, C White, K Twigger, M Coffey, B Thompson, S Kaye, J De-Bono (2005)A phase I study of a wild-type reovirus (Reolysin) given intravenously to patients with advanced malignancies., In: CLINICAL CANCER RESEARCH11(24)pp. 9106S-9107S
VK Agrawal, KM Copeland, Y Barbachano, A Rahim, R Seth, CL White, M Hingorani, CM Nutting, M Kelly, P Harris, H Pandha, AA Melcher, RG Vile, C Porter, KJ Harrington (2009)Microvascular free tissue transfer for gene delivery: in vivo evaluation of different routes of plasmid and adenoviral delivery, In: GENE THERAPY16(1)pp. 78-92 NATURE PUBLISHING GROUP
A Michael, K Syrigos, H Pandha (2009)Prostate cancer chemotherapy in the era of targeted therapy, In: PROSTATE CANCER AND PROSTATIC DISEASES12(1)pp. 13-16 NATURE PUBLISHING GROUP
S Hamdan, CS Verbeke, N Fox, J Booth, G Bottley, HS Pandha, GE Blair (2011)The roles of cell surface attachment molecules and coagulation Factor X in adenovirus 5-mediated gene transfer in pancreatic cancer cells., In: Cancer Gene Ther18(7)pp. 478-488
Transduction of 11 pancreatic cancer cell lines with a replication-deficient adenovirus 5 expressing enhanced green fluorescent protein (Ad5EGFP) was analyzed and variable EGFP levels were observed, ranging from <1% to ∼40% of cells transduced, depending on the cell line. Efficient Ad5EGFP transduction was associated mainly with higher levels of cell surface Coxsackie and adenovirus receptor (CAR) but not with expression of α(v)β(3) and α(v)β(5) integrins and was fiber dependent. Reduction of CAR by RNA interference resulted in a corresponding decrease in Ad5EGFP transduction. Pre-treatment of Ad5EGFP with blood coagulation Factor X increased virus entry even in the presence of low CAR levels generated by RNA interference, suggesting a potential alternative route of Ad5 entry into pancreatic cancer cells. Immunohistochemistry carried out on 188 pancreatic ductal adenocarcinomas and 68 matched controls showed that CAR was absent in 102 (54%) of adenocarcinomas, whereas moderate and strong staining was observed in 58 (31%) and 28 (15%) cases, respectively. Weak or absent CAR immunolabeling correlated with poor histological differentiation of pancreatic cancer. In normal tissue, strong immunolabeling was detected in islet cells and in the majority of inter- and intralobular pancreatic ducts.
A Dalgleish, H Pandha (2007)Tumor antigens as surrogate markers and targets for therapy and vaccines, In: ADVANCES IN CANCER RESEARCH, VOL 9696pp. 175-190 ELSEVIER ACADEMIC PRESS INC
MC Errico, F Felicetti, L Bottero, G Mattia, N Felli, M Petrini, M Bellenghi, HS Pandha, R Morgan, A Care (2014)THE ABROGATION OF THE HOXB7/PBX2 COMPLEX INDUCES APOPTOSIS IN MELANOMA THROUGH THE MIR-221&222-c-FOS PATHWAY, In: ANTICANCER RESEARCH34(10)pp. 5895-5896 INT INST ANTICANCER RESEARCH
Fredrick R. Schumacher, Ali Amin Al Olama, Sonja I. Berndt, Sara Benlloch, Mahbubl Ahmed, Edward J. Saunders, Tokhir Dadaev, Daniel Leongamornlert, Ezequiel Anokian, Clara Cieza-Borrella, Chee Goh, Mark N. Brook, Xin Sheng, Laura Fachal, Joe Dennis, Jonathan Tyrer, Kenneth Muir, Artitaya Lophatananon, Victoria L. Stevens, Susan M. Gapstur, Brian D. Carter, Catherine M. Tangen, Phyllis J. Goodman, Ian M. Thompson, Jyotsna Batra, Suzanne Chambers, Leire Moya, Judith Clements, Lisa Horvath, Wayne Tilley, Gail P. Risbridger, Henrik Gronberg, Markus Aly, Tobias Nordström, Paul Pharoah, Nora Pashayan, Johanna Schleutker, Teuvo L. J. Tammela, Csilla Sipeky, Anssi Auvinen, Demetrius Albanes, Stephanie Weinstein, Alicja Wolk, Niclas Håkansson, Catharine M. L. West, Alison M. Dunning, Neil Burnet, Lorelei A. Mucci, Edward Giovannucci, Gerald L. Andriole, Olivier Cussenot, Géraldine Cancel-Tassin, Stella Koutros, Laura E. Beane Freeman, Karina Dalsgaard Sorensen, Torben Falck Orntoft, Michael Borre, Lovise Maehle, Eli Marie Grindedal, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Richard M. Martin, Ruth C. Travis, Tim J. Key, Robert J. Hamilton, Neil E. Fleshner, Antonio Finelli, Sue Ann Ingles, Mariana C. Stern, Barry S. Rosenstein, Sarah L. Kerns, Harry Ostrer, Yong-Jie Lu, Hong-Wei Zhang, Ninghan Feng, Xueying Mao, Xin Guo, Guomin Wang, Zan Sun, Graham G. Giles, Melissa C. Southey, Robert J. MacInnis, Liesel M. FitzGerald, Adam S. Kibel, Bettina F. Drake, Ana Vega, Antonio Gómez-Caamaño, Robert Szulkin, Martin Eklund, Manolis Kogevinas, Javier Llorca, Gemma Castaño-Vinyals, Kathryn L. Penney, Meir Stampfer, Jong Y. Park, Thomas A. Sellers, Hui-Yi Lin, Janet L. Stanford, Cezary Cybulski, Dominika Wokolorczyk, Jan Lubinski, Elaine A. Ostrander, Milan S. Geybels, Børge G. Nordestgaard, Sune F. Nielsen, Maren Weischer, Rasmus Bisbjerg, Martin Andreas Røder, Peter Iversen, Hermann Brenner, Katarina Cuk, Bernd Holleczek, Christiane Maier, Manuel Luedeke, Thomas Schnoeller, Jeri Kim, Christopher J. Logothetis, Esther M. John, Manuel R. Teixeira, Paula Paulo, Marta Cardoso, Susan L. Neuhausen, Linda Steele, Yuan Chun Ding, Kim De Ruyck, Gert De Meerleer, Piet Ost, Azad Razack, Jasmine Lim, Soo-Hwang Teo, Daniel W. Lin, Lisa F. Newcomb, Davor Lessel, Marija Gamulin, Tomislav Kulis, Radka Kaneva, Nawaid Usmani, Sandeep Singhal, Chavdar Slavov, Vanio Mitev, Matthew Parliament, Frank Claessens, Steven Joniau, Thomas Van den Broeck, Samantha Larkin, Paul A. Townsend, Claire Aukim-Hastie, Manuela Gago Dominguez, Jose Esteban Castelao, Maria Elena Martinez, Monique J. Roobol, Guido Jenster, Ron H. N. van Schaik, Florence Menegaux, Thérèse Truong, Yves Akoli Koudou, Jianfeng Xu, Kay-Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Agnieszka Michael, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Sara Lindstrom, Constance Turman, Jing Ma, David J. Hunter, Elio Riboli, Afshan Siddiq, Federico Canzian, Laurence N. Kolonel, Loic Le Marchand, Robert N. Hoover, Mitchell J. Machiela, Zuxi Cui, Peter Kraft, Christopher I. Amos, David V. Conti, Douglas F. Easton, Fredrik Wiklund, Stephen J. Chanock, Brian E. Henderson, Zsofia Kote-Jarai, Christopher A. Haiman, Rosalind A. Eeles (2018)Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci, In: Nature Genetics50(7)pp. 928-936 Nature Publishing Group
Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P ˂ 5.0 × 10−8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10−9; G˃C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10−9; T˃G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55–2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04–6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa.
HS Pandha, A Protheroe, J Wylie, C Parker, J Chambers, S Bell, G Munzert (2008)An open label phase II trial of BI 2536, a novel Plk1 inhibitor, in patients with metastatic hormone refractory prostate cancer (HRPC), In: JOURNAL OF CLINICAL ONCOLOGY26(15) AMER SOC CLINICAL ONCOLOGY
M Hingorani, CL White, S Zaidi, A Merron, I Peerlinck, ME Gore, CM Nutting, HS Pandha, AA Melcher, RG Vile, G Vassaux, KJ Harrington (2008)Radiation-mediated up-regulation of gene expression from replication-defective adenoviral vectors: Implications for sodium iodide symporter gene therapy, In: CLINICAL CANCER RESEARCH14(15)pp. 4915-4924 AMER ASSOC CANCER RESEARCH
R Morgan, S Gray, C Gillett, Z Tabi, F Launchbury, J Spicer, K Harrington, HS Pandha (2014)HOX TRANSCRIPTION FACTORS ARE POTENTIAL TARGETS AND MARKERS IN MALIGNANT MESOTHELIOMA, In: ANTICANCER RESEARCH34(10)pp. 6069-6071 INT INST ANTICANCER RESEARCH
C Alamara, EM Karapanagiotou, I Tourkantonis, V Xyla, CC Maurer, M Lykourinas, H Pandha, KN Syrigos (2008)Renal oncocytoma: a case report and short review of the literature., In: Eur J Intern Med19(7)pp. e67-e69
C Lunt, N Barber, A Montgomery, V Kalsi, T Parker, A Michael, H Pandha, R Hindley (2010)CYTOREDUCTIVE NEPHRECTOMY IN THE TYROKINASE INHIBITOR ERA, In: J ENDOUROL24pp. A303-A303 MARY ANN LIEBERT INC
R Morgan, G Simpson, S Gray, C Gillett, Z Tabi, J Spicer, KJ Harrington, HS Pandha (2016)HOX transcription factors are potential targets and markers in malignant mesothelioma, In: BMC CANCER16ARTN 85 BIOMED CENTRAL LTD
ADM Ross, MG Cook, H Chong, M Hossain, HS Pandha, DC Bennett (2013)Senescence evasion in melanoma progression: uncoupling of DNA-damage signaling from p53 activation and p21 expression, In: PIGMENT CELL & MELANOMA RESEARCH26(2) WILEY-BLACKWELL
R Morgan, A Boxall, A Bhatt, M Bailey, R Hindley, S Langley, HC Whitaker, DE Neal, M Ismail, H Whitaker, N Annels, A Michael, H Pandha (2011)Engrailed-2 (EN2): A Tumor Specific Urinary Biomarker for the Early Diagnosis of Prostate Cancer, In: CLINICAL CANCER RESEARCH17(5)pp. 1090-1098 AMER ASSOC CANCER RESEARCH
N Quatan, B Meyer, M Bailey, H Pandha (2006)Persistently high levels of immunosuppressive cytokines in patients after radical prostatectomy, In: PROSTATE CANCER AND PROSTATIC DISEASES9(4)pp. 420-425 NATURE PUBLISHING GROUP
Richard Morgan, RT Bryan, S Javed, F Launchbury, MP Zeegers, KK Cheng, ND James, DM Wallace, CD Hurst, DG Ward, MA Knowles, Hardev Pandha (2013)Expression of Engrailed-2 (EN2) protein in bladder cancer and its potential utility as a urinary diagnostic biomarker., In: Eur J Cancer Elsevier
Despite significant advances in our understanding of the molecular pathology of bladder cancer, it remains a significant health problem with high morbidity and mortality associated with muscle-invasive bladder cancer (stages T2+), and high costs associated with the surveillance of non-muscle-invasive bladder cancer (NMIBC, stages Ta/T1/Tis). Moreover, current diagnostic biomarkers are suboptimal and of poor utility for low grade disease and surveillance. In this study, we show that the Engrailed-2 (EN2) transcription factor is expressed in, and secreted by, bladder cancer cell lines and patient tumour specimens, justifying an evaluation of urinary EN2 as a diagnostic biomarker in bladder cancer using archived samples from an established biospecimen collection. In patients with NMIBC, urinary EN2 was detected in most cases with an overall sensitivity of 82% and specificity of 75%. The sensitivity for stage Ta and T1 tumours was 71% and 76%, respectively, and 94% for stage T2+ tumours. This compares favourably with existing markers. The sensitivity for tumour grades 1, 2 and 3 was 69%, 78% and 87%, respectively. Thus urinary EN2 has the potential to be a more sensitive and specific protein biomarker for NMIBC than currently available tests.
D Enting, ML Lannitto, HS Pandha, M Eberi, S Chowdhury, AC Hayday (2014)Effects of concomitant therapies on gamma delta T-cell responses to zoledronate in patients with advanced prostate cancer, In: JOURNAL OF CLINICAL ONCOLOGY32(15)
S Chowdhury, H Pandha (2006)Targeting renal cell carcinoma, In: CLINICAL ONCOLOGY18(7)pp. 511-512 ELSEVIER SCIENCE LONDON
Z Kelly, H Pandha, K Madhuri, R Morgan, A Michael (2012)HOX GENE EXPRESSION IN OVARIAN CANCER, In: ANNALS OF ONCOLOGY23pp. 68-68
S Zaidi, M Blanchard, K Shim, E Ilett, T Kottke, J Thompson, E Celis, H Pandha, P Selby, A Melcher, K Harrington, R Vile (2014)Acquisition of Mutated BRAF Is as a Major Effector of Melanoma Recurrence Which Can Be Targeted By Immuno- or Chemo-Therapy, In: MOLECULAR THERAPY22pp. S245-S245
V Roulstone, K Khan, HS Pandha, S Rudman, M Coffey, GM Gill, AA Melcher, R Vile, KJ Harrington, J de Bono, J Spicer (2015)Phase I Trial of Cyclophosphamide as an Immune Modulator for Optimizing Oncolytic Reovirus Delivery to Solid Tumors, In: CLINICAL CANCER RESEARCH21(6)pp. 1305-1312 AMER ASSOC CANCER RESEARCH
A Michael, K Relph, H Pandha (2010)Emergence of potential biomarkers of response to anti-angiogenic anti-tumour agents., In: International Journal of Cancer127(6)pp. 1251-1258 Wiley-Blackwell
Anti-angiogenic agents targeting tumour vasculature have an established place in clinical practice, and new data are constantly emerging. However, despite rapid clinical uptake, a very large number of questions regarding these agents remain unanswered. One of the main hurdles in clinical practice is lack of accurate and feasible ways of assessing response to drug beyond tumour reduction on conventional imaging. This review summarises recent developments in the field of biomarkers of response to anti-VEGF drugs.
OG Donnelly, F Errington-Mais, L Steele, E Hadac, V Jennings, K Scott, H Peach, RM Phillips, J Bond, H Pandha, K Harrington, R Vile, S Russell, P Selby, AA Melcher (2011)Measles virus causes immunogenic cell death in human melanoma., In: Gene Ther
Oncolytic viruses (OV) are promising treatments for cancer, with several currently undergoing testing in randomised clinical trials. Measles virus (MV) has not yet been tested in models of human melanoma. This study demonstrates the efficacy of MV against human melanoma. It is increasingly recognised that an essential component of therapy with OV is the recruitment of host antitumour immune responses, both innate and adaptive. MV-mediated melanoma cell death is an inflammatory process, causing the release of inflammatory cytokines including type-1 interferons and the potent danger signal HMGB1. Here, using human in vitro models, we demonstrate that MV enhances innate antitumour activity, and that MV-mediated melanoma cell death is capable of stimulating a melanoma-specific adaptive immune response.Gene Therapy advance online publication, 15 December 2011; doi:10.1038/gt.2011.205.
E Derhovanessian, V Adams, K Haehnel, A Groeger, H Pandha, S Ward, G Pawelec (2009)Pretreatment frequency of circulating IL-17(+)CD4(+) T-cells, but not Tregs, correlates with clinical response to whole-cell vaccination in prostate cancer patients, In: INTERNATIONAL JOURNAL OF CANCER125(6)pp. 1372-1379 WILEY-BLACKWELL
M Ismail, S Bokaee, R Morgan, J Davies, KJ Harrington, H Pandha (2009)Inhibition of the aquaporin 3 water channel increases the sensitivity of prostate cancer cells to cryotherapy (vol 100, pg 1889, 2009), In: BRITISH JOURNAL OF CANCER101(3)pp. 549-549 NATURE PUBLISHING GROUP
H Pandha, L Birchall, B Meyer, N Wilson, K Relph, C Anderson, K Harrington (2006)Antitumor effects of aminobisphosphonates on renal cell carcinoma cell lines, In: JOURNAL OF UROLOGY176(5)pp. 2255-2261 ELSEVIER SCIENCE INC
C Comins, L Heinemann, K Harrington, A Melcher, J De Bono, H Pandha (2008)Reovirus: Viral therapy for cancer 'as nature intended', In: CLINICAL ONCOLOGY20(7)pp. 548-554 ELSEVIER SCIENCE LONDON
A Michael, ZL Kelly, CS Moller-Levet, H Pandha, R Morgan (2014)HOX GENE EXPRESSION IN OVARIAN CANCER, In: ANTICANCER RESEARCH34(10)pp. 6058-6059 INT INST ANTICANCER RESEARCH
T Kottke, G Hall, J Pulido, RM Diaz, J Thompson, H Chong, P Selby, M Coffey, H Pandha, J Chester, A Melcher, K Harrington, R Vile (2010)Antiangiogenic cancer therapy combined with oncolytic virotherapy leads to regression of established tumors in mice, In: JOURNAL OF CLINICAL INVESTIGATION120(5)pp. 1551-1560 AMER SOC CLINICAL INVESTIGATION INC
Agnieszka Michael, Kate Relph, Nicola Annels, Hardev Pandha (2014)Prostate cancer vaccines., In: Expert Review of Vaccines12(3)pp. 253-262 Taylor & Francis
In 2010, the US FDA approved the first therapeutic cancer vaccine for the treatment of castration refractory prostate cancer - sipuleucel-T. Prostate cancer is an ideal model for cancer vaccine development based on the ready demonstration of humoral and cellular immunity to a range of cancer antigens as well as often slow progression which means that patients who are otherwise well may have a radiologically evaluable minor progression, after conventional treatment and can undergo vaccine therapy over sufficient periods of time, so as to allow the generation of a robust antitumor response. The association of prostate cancer with one of the few serum cancer biomarkers in general use has also allowed assessment of response and risk stratification of patients. In this review, we will examine key aspects of the evolution of prostate cancer vaccines, which provides an accurate prototype for other cancers, and the challenges we face.
C Comins, J Spicer, A Protheroe, V Roulstone, K Twigger, CM White, R Vile, A Melcher, MC Coffey, KL Mettinger, G Nuovo, DE Cohn, M Phelps, KJ Harrington, HS Pandha (2010)REO-10: A Phase I Study of Intravenous Reovirus and Docetaxel in Patients with Advanced Cancer, In: CLINICAL CANCER RESEARCH16(22)pp. 5564-5572 AMER ASSOC CANCER RESEARCH
Louise M. E. Müller, Matthew Holmes, Joanne L. Michael, Gina B. Scott, Emma J. West, Karen J. Scott, Christopher Parrish, Kathryn Halliwell, Sina Stäble, Victoria A. Jennings, Matthew Cullen, Stewart McConnell, Catherine Langton, Emma L. Tidswell, Darren Shafren, Adel Samson, Kevin J. Harrington, Hardev Pandha, Christy Ralph, Richard J. Kelly, Gordon Cook, Alan A. Melcher, Fiona Errington-Mais (2019)Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21, In: Journal for ImmunoTherapy of Cancer7164pp. 1-16 BMC
Background
The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible.
Methods
This study utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, and iii) patients taking part in the STORM clinical trial, who received intravenous CVA21; patients receiving intravenous CVA21 were consented separately in accordance with local institutional ethics review and approval. Collectively, these blood samples were used to characterize the development of innate and adaptive anti-tumor immune responses following CVA21 treatment.
Results
An Initial characterization of peripheral blood mononuclear cells, collected from cancer patients following intravenous infusion of CVA21, confirmed that CVA21 activated immune effector cells in patients. Next, using hematological disease models which were sensitive (Multiple Myeloma; MM) or resistant (AML) to CVA21-direct oncolysis, we demonstrated that CVA21 stimulated potent anti-tumor immune responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cellular cytotoxicity; and 3) priming of tumor-specific cytotoxic T lymphocytes, with specificity towards known tumor-associated antigens. Importantly, immune-mediated killing of both MM and AML, despite AML cells being resistant to CVA21-direct oncolysis, was observed. Upon further examination of the cellular mechanisms responsible for CVA21-induced anti-tumor immunity we have identified the importance of type I IFN for NK cell activation, and demonstrated that both ICAM-1 and plasmacytoid dendritic cells were key mediators of this response.
Conclusion
This work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations.
T Kottke, F Errington, J Pulido, F Galivo, J Thompson, P Wongthida, RM Diaz, H Chong, E Ilett, J Chester, H Pandha, K Harrington, P Selby, A Melcher, R Vile (2011)Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors., In: Nat Med17(7)pp. 854-859
Effective cancer immunotherapy requires the release of a broad spectrum of tumor antigens in the context of potent immune activation. We show here that a cDNA library of normal tissue, expressed from a highly immunogenic viral platform, cures established tumors of the same histological type from which the cDNA library was derived. Immune escape occurred with suboptimal vaccination, but tumor cells that escaped the immune pressure were readily treated by second-line virus-based immunotherapy. This approach has several major advantages. Use of the cDNA library leads to presentation of a broad repertoire of (undefined) tumor-associated antigens, which reduces emergence of treatment-resistant variants and also permits rational, combined-modality approaches in the clinic. Finally, the viral vectors can be delivered systemically, without the need for tumor targeting, and are amenable to clinical-grade production. Therefore, virus-expressed cDNA libraries represent a novel paradigm for cancer treatment addressing many of the key issues that have undermined the efficacy of immuno- and virotherapy to date.
KJ Harrington, A Melcher, G Vassaux, HS Pandha, RG Vile (2008)Exploiting synergies between radiation and oncolytic viruses, In: CURRENT OPINION IN MOLECULAR THERAPEUTICS10(4)pp. 362-370 THOMSON SCIENTIFIC
G Balls, N Quatan, A Michael, L Lancashire, V Adams, B Hoffman, C Pfirschke, N Russell, M Whelan, H Pandha (2007)Immunological response patterns correlate with clinical outcome after allogeneic vaccination in hormone resistant prostate cancer metastatic to bone, In: JOURNAL OF IMMUNOTHERAPY30(8)pp. 891-891
J Qiao, H Wang, T Kottke, C White, K Twigger, RM Diaz, J Thompson, P Selby, J de Bono, A Melcher, H Pandha, M Coffey, R Vile, K Harrington (2008)Cyclophosphamide facilitates antitumor efficacy against subcutaneous tumors following intravenous delivery of reovirus, In: CLINICAL CANCER RESEARCH14(1)pp. 259-269 AMER ASSOC CANCER RESEARCH
M Ismail, S Ahmed, R Laing, R Nigam, S Langley, H Pandha, J Davies (2007)Antibody immunity to prostate cancer specific antigen in the serum of patients having cryotherapy or brachytherapy treatment compared to healthy volunteers, In: BJU INTERNATIONAL99pp. 47-48
L Plowright, K Harrington, HS Pandha, R Morgan HOX transcription factors are potential therapeutic targets in non-small cell lung cancer, In: British Journal of Cancer Nature Publishing Group
The HOX genes are a family of homeodomain-containing transcription factors that determine the identity of cells and tissues during embryonic development. They are also known to behave as oncogenes in some haematological malignancies. In this study we show that the expression of many of the HOX genes is highly elevated in primary non-small cell lung cancers and in the derived cell lines A549 and H23. Furthermore, blocking the activity of HOX proteins by interfering with their binding to the PBX co-factor causes these cells to undergo apoptosis in vitro and reduces the growth of A549 tumours in vivo. These findings suggest that the interaction between HOX and PBX proteins is a potential therapeutic target in non-small cell lung cancer.
D Harris, L Vidal, A Melcher, K Newbold, A Anthony, V Karavasilis, R Agarwal, C White, K Twigger, M Coffey, K Mettinger, B Thompson, H Pandha, J De-Bono, K Harrington (2007)A Phase I study to evaluate the feasibility, safety and biological effects of intratumoural administration of wild-type Reovirus (REOLYSIN (R)) in combination with radiation in patients with advanced malignancies., In: MOLECULAR CANCER THERAPEUTICS6(12)pp. 3458S-3458S AMER ASSOC CANCER RESEARCH
KL Relph, KJ Harrington, H Pandha (2005)Adenoviral strategies for the gene therapy of cancer, In: SEMINARS IN ONCOLOGY32(6)pp. 573-582 W B SAUNDERS CO
SE McGrath, A Michael, R Morgan, H Pandha (2013)EN2: a novel prostate cancer biomarker., In: Biomark Med7(6)pp. 893-901
Extensive efforts to identify a clinically useful biomarker for the diagnosis of prostate cancer have resulted in important insights into the biology of the disease, but no new test has been approved by regulatory authorities. The unmet need has also shifted to identifying biomarkers that not only diagnose prostate cancer but also indicate whether the patient has 'significant' disease. EN2 is a homeobox-containing transcription factor secreted specifically by prostate cancers into urine, where it can be detected by a simple ELISA assay. A number of studies have demonstrated the enormous potential of EN2 to address this unmet need and provide the urologist with a simple, cheap and efficient prostate cancer biomarker.
EG Havranek, M-C Labarthe, S Ward, CJ Anderson, MA Whelan, H Pandha (2008)A novel murine model of allogeneic vaccination against renal cancer, In: BJU INTERNATIONAL101(9)pp. 1165-1169 BLACKWELL PUBLISHING
TA Yap, A Brunetto, H Pandha, K Harrington, JS de Bono (2008)Reovirus therapy in cancer: has the orphan virus found a home?, In: EXPERT OPINION ON INVESTIGATIONAL DRUGS17(12)pp. 1925-1935 INFORMA HEALTHCARE
L Heinemann, GR Simpson, A Boxall, T Kottke, KL Relph, R Vile, A Melcher, R Prestwich, KJ Harrington, R Morgan, HS Pandha (2011)Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer., In: BMC Cancer11pp. 221-? Biomed Central
Reovirus type 3 Dearing (T3D) has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication.
TR Daniels, II Neacato, JA Rodriguez, HS Pandha, R Morgan, ML Penichet (2014)TARGETING THE HOX TRANSCRIPTION FACTORS AND CD71 IN MULTIPLE MYELOMA, In: ANTICANCER RESEARCH34(10)pp. 6107-6108 INT INST ANTICANCER RESEARCH
CJ Bull, C Bonilla, JM Holly, CM Perks, N Davies, P Haycock, OH Yu, JB Richards, R Eeles, D Easton, Z Kote-Jarai, A Amin Al Olama, S Benlloch, K Muir, GG Giles, RJ MacInnis, F Wiklund, H Gronberg, CA Haiman, J Schleutker, BG Nordestgaard, RC Travis, D Neal, N Pashayan, KT Khaw, JL Stanford, WJ Blot, S Thibodeau, C Maier, AS Kibel, C Cybulski, L Cannon-Albright, H Brenner, J Park, R Kaneva, J Batra, MR Teixeira, A Micheal, H Pandha, GD Smith, SJ Lewis, RM Martin (2016)Blood lipids and prostate cancer: a Mendelian randomization analysis., In: Cancer medicine5(6)pp. 1125-1136
Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916-T variant in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy.
L Vidal, H Pandha, J Spicer, KJ Harrington, S Allen, D Leader, M Coffey, B Thompson, S Kaye, J De-Bono (2006)A phase I study of reolysin given intravenously to patients with advanced malignancies., In: JOURNAL OF CLINICAL ONCOLOGY24(18)pp. 136S-136S
GR Simpson, A Horvath, K Harrington, RS Coffin, H Pandha (2008)Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer, In: EJC SUPPLEMENTS6(12)pp. 97-98
GS Papaetis, LM Karapanagiotou, H Pandha, KN Syrigos (2008)Targeted therapy for advanced renal cell cancer: Cytokines and beyond, In: CURRENT PHARMACEUTICAL DESIGN14(22)pp. 2229-2251 BENTHAM SCIENCE PUBL LTD
R Morgan, B Fairfax, HS Pandha (2006)Calcium insensitivity of FA-6, a cell line derived from a pancreatic cancer associated with humoral hypercalcemia, is mediated by the significantly reduced expression of the Calcium Sensitive Receptor transduction component p38 MAPK, In: MOLECULAR CANCER5ARTN 5pp. ?-? BIOMED CENTRAL LTD
M Hingorani, C Spitzweg, G Vassaux, K Newbold, A Melcher, H Pandha, R Vile, K Harrington (2010)The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery, In: CURR CANCER DRUG TAR10(2)pp. 242-267 BENTHAM SCIENCE PUBL LTD
H Pandha, A Melcher, K Harrington, R Vile (2009)Oncolytic Viruses: Time to Compare, Contrast, and Combine?, In: MOLECULAR THERAPY17(6)pp. 934-935 NATURE PUBLISHING GROUP
A Horvath, GR Simpson, RS Coffin, AH Mostafid, H Pandha (2011)Update on a novel intravesical therapy for non muscle invasive bladder cancer: Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic herpes simplex virus, In: BRITISH JOURNAL OF SURGERY98(6)pp. E2-E2
J Spicer, T Plunkett, N Somaiah, S Chan, A Kendall, N Bolunwu, H Pandha (2005)Phase II study of oral capecitabine in patients with hormone-refractory prostate cancer, In: PROSTATE CANCER AND PROSTATIC DISEASES8(4)pp. 364-368 NATURE PUBLISHING GROUP
HS Pandha, KJ Harrington, RG Vile (2008)Poxviruses as immunomodulatory cancer therapeutics., In: Viral Therapy of Cancer
T Pencavel, R Seth, A Hayes, A Melcher, H Pandha, R Vile, KJ Harrington (2010)Locoregional intravascular viral therapy of cancer: precision guidance for Paris's arrow?, In: GENE THERAPY17(8)pp. 949-960 NATURE PUBLISHING GROUP
E Koropouli, L Manolopoulus, H Pandha, KN Syrigos (2009)The biological role of mTOR in the pathogenesis of solid tumors: An overview, In: Current Enzyme Inhibition5(1)pp. 51-65
D George, J-F Martini, M Staehler, R Motzer, A Magheli, B Escudier, P Gerletti, S Li, M Casey, B Laguerre, Hardev Pandha, A Pantuck, A Patel, M Lechuga, A Ravaud (2018)Immune biomarkers predictive for disease-free survival with adjuvant sunitinib in high-risk locoregional renal cell carcinoma: from randomized phase III S-TRAC study, In: Clinical Cancer Research American Association for Cancer Research
Purpose: Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma in the S-TRAC trial (ClinicalTrials.gov number, NCT00375674). A prospectively-designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit. Experimental Design: Tissue blocks were used for immunohistochemistry (IHC) staining of PD-L1, CD4, CD8, and CD68. DFS was compared between < versus ≥ median IHC parameter using the Kaplan–Meier method. For biomarkers with predictive potential, Receiver Operating Characteristics curves were generated. Results: Baseline characteristics were similar in patients with (n=191) and without (n=419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8+ T-cell density ≥ versus < median (median [95% CI], not reached [6.83–not reached] vs. 3.47 years [1.73–not reached]; hazard ratio 0.40 [95% CI, 0.20–0.81]; P=0.009) treated with sunitinib (n=101), but not with placebo (n=90). The sensitivity and specificity for CD8+ T-cell density in predicting DFS were 0.604 and 0.658, respectively. Shorter DFS was observed in placebo-treated patients with PD-L1+ versus PD-L1– tumors (hazard ratio 1.75; P=0.103). Among all patients with PD-L1+ tumors, DFS was numerically longer with sunitinib versus placebo (hazard ratio 0.58; P=0.175). Conclusions: Greater CD8+ T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk non-metastatic renal cell carcinoma should also be further explored.
TA Yap, L Vidal, H Pandha, J Spicer, L Digue, M Coffey, B Thompson, SB Kaye, KJ Harrington, JS De-Bono (2006)A phase I study of wild-type reovirus, which selectively replicates in cells expressing activated Ras, administered intravenously to patients with advanced cancer, In: EJC SUPPLEMENTS4(12)pp. 108-108 PERGAMON-ELSEVIER SCIENCE LTD
RJ Prestwich, EJ Ilett, F Errington, RM Diaz, LP Steele, T Kottke, J Thompson, F Galivo, KJ Harrington, HS Pandha, PJ Selby, RG Vile, AA Melcher (2009)Immune-Mediated Antitumor Activity of Reovirus Is Required for Therapy and Is Independent of Direct Viral Oncolysis and Replication, In: CLINICAL CANCER RESEARCH15(13)pp. 4374-4381 AMER ASSOC CANCER RESEARCH
CL White, KR Twigger, L Vidal, JS De Bono, M Coffey, L Heinemann, R Morgan, A Merrick, F Errington, RG Vile, AA Melcher, HS Pandha, KJ Harrington (2008)Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial, In: GENE THERAPY15(12)pp. 911-920 NATURE PUBLISHING GROUP
Aadil A. Khan, James T. Paget, Martin McLaughlin, Joan N. Kyula, Michelle J. Wilkinson, Timothy Pencavel, David Mansfield, Victoria Roulstone, Rohit Seth, Martin Halle, Navita Somaiah, Jessica K. R. Boult, Simon P. Robinson, Hardev Pandha, Richard G. Vile, Alan A. Melcher, Paul A. Harris, Kevin J. Harrington (2018)Genetically modified lentiviruses that preserve microvascular function protect against late radiation damage in normal tissues, In: Science Translational Medicine10(425) American Association for the Advancement of Science
Improvements in cancer survival mean that long-term toxicities, which contribute to the morbidity of cancer survivorship, are being increasingly recognized. Late adverse effects (LAEs) in normal tissues after radiotherapy (RT) are characterized by vascular dysfunction and fibrosis causing volume loss and tissue contracture, for example, in the free flaps used for immediate breast reconstruction after mastectomy. We evaluated the efficacy of lentivirally delivered superoxide dismutase 2 (SOD2) overexpression and connective tissue growth factor (CTGF) knockdown by short hairpin RNA in reducing the severity of LAEs in an animal model of free flap LAEs. Vectors were delivered by intra-arterial injection, ex vivo, to target the vascular compartment. LVSOD2 and LVshCTGF monotherapy before irradiation resulted in preservation of flap volume or reduction in skin contracture, respectively. Flaps transduced with combination therapy experienced improvements in both volume loss and skin contracture. Both therapies reduced the fibrotic burden after irradiation. LAEs were associated with impaired vascular perfusion, loss of endothelial permeability, and stromal hypoxia, which were all reversed in the treatment model. Using a tumor recurrence model, we showed that SOD2 overexpression in normal tissues did not compromise the efficacy of RT against tumor cells but appeared to enhance it. LVSOD2 and LVshCTGF combination therapy by targeted, intravascular delivery reduced LAE severities in normal tissues without compromising the efficacy of RT and warrants translational evaluation as a free flap–targeted gene therapy.
Nicola Annels, Mehreen Arif, Guy Simpson, Mick Denyer, Carla Moller-Levet, David Mansfield, Rachel Butler, Darren Shafren, Gough Au, Margaret Knowles, Kevin Harrington, Richard Vile, Alan Melcher, Hardev Pandha (2018)Oncolytic Immunotherapy for Bladder Cancer Using Coxsackie A21 Virus, In: Molecular Therapy - Oncolytics9pp. 1-12 Elsevier
As a clinical setting in which local live biological therapy is already well established, non-muscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1)-targeted immunotherapeutic virus. This study investigated CVA21-induced cytotoxicity in a panel of human bladder cancer cell lines, revealing a range of sensitivities largely correlating with expression of the viral receptor ICAM-1. CVA21 in combination with low doses of mitomycin-C enhanced CVA21 viral replication and oncolysis by increasing surface expression levels of ICAM-1. This was further confirmed using 300-μm precision slices of NMIBC where levels of virus protein expression and induction of apoptosis were enhanced with prior exposure to mitomycin-C. Given the importance of the immunogenicity of dying cancer cells for triggering tumor-specific responses and long-term therapeutic success, the ability of CVA21 to induce immunogenic cell death was investigated. CVA21 induced immunogenic apoptosis in bladder cancer cell lines, as evidenced by expression of the immunogenic cell death (ICD) determinant calreticulin, and HMGB-1 release and the ability to reject MB49 tumors in syngeneic mice after vaccination with MB49 cells undergoing CVA21 induced ICD. Such CVA21 immunotherapy could offer a potentially less toxic, more effective option for the treatment of bladder cancer.
RJ Prestwich, KJ Scott, J Brown, P Harnden, P Whelan, J Cartledge, D O'Donnell, HS Pandha, PJ Selby, RE Banks, AE Merrick, AA Melcher (2009)The feasibility of establishing a programme of adjuvant autologous vaccination for renal cell carcinoma, In: BJU INTERNATIONAL103(6)pp. 740-746 WILEY-BLACKWELL PUBLISHING, INC
M Hingorani, CL White, A Merron, I Peerlinck, ME Gore, A Slade, SD Scott, CM Nutting, HS Pandha, AA Melcher, RG Vile, G Vassaux, KJ Harrington (2008)Inhibition of Repair of Radiation-Induced DNA Damage Enhances Gene Expression from Replication-Defective Adenoviral Vectors, In: CANCER RESEARCH68(23)pp. 9771-9778 AMER ASSOC CANCER RESEARCH
K Hall, KJ Scott, A Rose, M Desborough, K Harrington, H Pandha, C Parrish, R Vile, M Coffey, D Bowen, F Errington-Mais, AA Melcher (2012)Reovirus-mediated cytotoxicity and enhancement of innate immune responses against acute myeloid leukemia., In: Biores Open Access1(1)pp. 3-15
Reovirus is a naturally occurring oncolytic virus that has shown preclinical efficacy in the treatment of a wide range of tumor types and has now reached phase III testing in clinical trials. The anti-cancer activity of reovirus has been attributed to both its direct oncolytic activity and the enhancement of anti-tumor immune responses. In this study, we have investigated the direct effect of reovirus on acute myeloid leukemia (AML) cells and its potential to enhance innate immune responses against AML, including the testing of primary samples from patients. Reovirus was found to replicate in and kill AML cell lines, and to reduce cell viability in primary AML samples. The pro-inflammatory cytokine interferon alpha (IFNα) and the chemokine (C-C motif) ligand 5 (known as RANTES [regulated upon activation, normal T-cell expressed, and secreted]) were also secreted from AML cells in response to virus treatment. In addition, reovirus-mediated activation of natural killer (NK) cells, within the context of peripheral blood mononuclear cells, stimulated their anti-leukemia response, with increased NK degranulation and IFNγ production and enhanced killing of AML targets. These data suggest that reovirus has the potential as both a direct cytotoxic and an immunotherapeutic agent for the treatment of AML.
M Ismail, R Morgan, J Davies, H Pandha (2009)Inhibition of the aquaporin water channels (AQPs) increases the sensitivity of DU145 cells to cryotherapy, In: BJU INTERNATIONAL103pp. 21-21
RJ Prestwich, KJ Harrington, HS Pandha, RG Vile, AA Melcher, F Errington (2008)Oncolytic viruses: a novel form of immunotherapy, In: EXPERT REVIEW OF ANTICANCER THERAPY8(10)pp. 1581-1588 EXPERT REVIEWS
NE Annels, VE Shaw, RF Gabitass, L Billingham, P Corrie, M Eatock, J Valle, D Smith, J Wadsley, D Cunningham, H Pandha, JP Neoptolemos, G Middleton (2013)The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer., In: Cancer Immunol Immunother
In pre-clinical models, the only two chemotherapy drugs which have been demonstrated to directly reduce the number of myeloid-derived suppressor cells (MDSCs) are gemcitabine and 5-fluorouracil. Here we analyze the dynamics of MDSCs, phenotyped as Lin-DR-CD11b+, in patients with advanced pancreatic cancer receiving the combination of gemcitabine and capecitabine, a 5-FU pro-drug. We found no evidence that gemcitabine and capecitabine directly reduce MDSC% in patients. Gemcitabine and capecitabine reduced MDSCs in 42 % of patients (n = 19) and MDSC% fell in only 3/9 patients with above-median baseline MDSCs. In 5/8 patients with minimal tumour volume change on treatment, the MDSC% went up: increases in MDSC% in these patients appeared to correlate with sustained cancer-related inflammatory cytokine upregulation. In a separate cohort of 21 patients treated with gemcitabine and capecitabine together with concurrently administered GV1001 vaccine with adjuvant GM-CSF, the MDSC% fell in 18/21 patients and there was a significant difference in the trajectory of MDSCs between those receiving GV1001 and GM-CSF in combination with chemotherapy and those receiving chemotherapy alone. Thus, there was no evidence that the addition of low-dose adjuvant GM-CSF increased Lin-DR-CD11b+ MDSC in patients receiving combination chemoimmunotherapy. 9/21 patients developed an immune response to GV1001 and the MDSCs fell in 8 of these 9 patients, 6 of whom had above-median pre-vaccination MDSC levels. A high pre-vaccination MDSC% does not preclude the development of immunity to a tumour-associated antigen.
R Morgan, A Boxall, KJ Harrington, GR Simpson, A Michael, HS Pandha (2014)Targeting HOX transcription factors in prostate cancer, In: BMC UROLOGY14ARTN 1pp. ?-? BIOMED CENTRAL LTD
RA Alharbi, HS Pandha, R Morgan, R Pettengell (2013)The role of HOX genes in normal hematopoiesis and acute leukemia, In: Leukemia27(5)pp. 1000-1008
The homeobox (HOX) genes are a highly conserved family of homeodomain-containing transcription factors that specify cell identity in early development and, subsequently, in a number of adult processes including hematopoiesis. The dysregulation of HOX genes is associated with a number of malignancies including acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), where they have been shown to support the immortalization of leukemic cells both as chimeric partners in fusion genes and when overexpressed in their wild-type form. This review covers our current understanding of the role of HOX genes in normal hematopoiesis, AML and ALL, with particular emphasis on the similarities and differences of HOX function in these contexts, their hematopoietic downstream gene targets and implications for therapy. © 2013 Macmillan Publishers Limited All rights reserved.
E Ilett, T Kottke, O Donnelly, J Thompson, C Willmon, R Diaz, S Zaidi, M Coffey, P Selby, K Harrington, H Pandha, A Melcher, R Vile (2014)Cytokine Conditioning Enhances Systemic Delivery and Therapy of an Oncolytic Virus, In: MOLECULAR THERAPY22(10)pp. 1851-1863 NATURE PUBLISHING GROUP
EM Karapanagiotou, V Roulstone, K Twigger, M Ball, M Tanay, C Nutting, K Newbold, ME Gore, J Larkin, KN Syrigos, M Coffey, B Thompson, K Mettinger, RG Vile, HS Pandha, GD Hall, AA Melcher, J Chester, KJ Harrington (2012)Phase I/II Trial of Carboplatin and Paclitaxel Chemotherapy in Combination with Intravenous Oncolytic Reovirus in Patients with Advanced Malignancies, In: CLINICAL CANCER RESEARCH18(7)pp. 2080-2089 AMER ASSOC CANCER RESEARCH
V Roulstone, K Twigger, S Zaidi, T Pencavel, JN Kyula, C White, M McLaughlin, R Seth, EM Karapanagiotou, D Mansfield, M Coffey, G Nuovo, RG Vile, HS Pandha, AA Melcher, KJ Harrington (2012)Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin-paclitaxel doublet chemotherapy., In: Gene Ther
Oncolytic reovirus is currently under active investigation in a range of tumour types. Early phase studies have shown that this agent has modest monotherapy efficacy and its future development is likely to focus on combination regimens with cytotoxic chemotherapy. Indeed, phase I/II clinical trials have confirmed that reovirus can be safely combined with cytotoxic drugs, including a platin-taxane doublet regimen, which is currently being tested in a phase III clinical trial in patients with relapsed/metastatic head and neck cancer. Therefore, we have tested this triple (reovirus, cisplatin, paclitaxel) combination therapy in a panel of four head and neck cancer cell lines. Using the combination index (CI) method, the triple therapy demonstrated synergistic cytotoxicity in vitro in both malignant and non-malignant cell lines. In head and neck cancer cell lines, this was associated with enhanced caspase 3 and 7 cleavage, but no increase in viral replication. In vitro analyses confirmed colocalisation of markers of reovirus infection and caspase 3. Triple therapy was significantly more effective than reovirus or cisplatin-paclitaxel in athymic nude mice. These data suggest that the combination of reovirus plus platin-taxane doublet chemotherapy has significant activity in head and neck cancer and underpin the current phase III study in this indication.Gene Therapy advance online publication, 16 August 2012; doi:10.1038/gt.2012.68.
Richard Morgan, A Boxall, Guy Simpson, Agnieszka Michael, Hardev Pandha, KJ Harrington, C Gillett (2012)Targeting the HOX/PBX dimer in breast cancer, In: Breast Cancer Research and Treatment136(2)pp. 389-398 Springer Verlag
The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in a number of malignancies, including breast cancer. While relatively little is known about the roles that individual HOX genes play in cancer, it is however clear that these roles can be both contradictory, with some members acting as oncogenes and some as tumor suppressors, and also redundant, with several genes essentially having the same function. Here, we have attempted to address this complexity using the HXR9 peptide to target the interaction between HOX proteins and PBX, a second transcription factor that serves as a common co-factor for many HOX proteins. We show that HXR9 causes apoptosis in a number of breast cancer-derived cell lines and that sensitivity to HXR9 is directly related to the averaged expression of HOX genes HOXB1 through to HOXB9, providing a potential biomarker to predict the sensitivity of breast tumors to HXR9 or its derivatives. Measuring the expression of HOX genes HOXB1-HOXB9 in primary tumors revealed that a subset of tumors show highly elevated expression indicating that these might be potentially very sensitive to killing by HXR9. Furthermore, we show that while HXR9 blocks the oncogenic activity of HOX genes, it does not affect the known tumor-suppressor properties of a subset of HOX genes in breast cancer.
GR Simpson, A Horvath, NE Annels, T Pencavel, S Metcalf, R Seth, P Peschard, T Price, RS Coffin, H Mostafid, AA Melcher, KJ Harrington, HS Pandha (2012)Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer, In: BRITISH JOURNAL OF CANCER106(3)pp. 496-507
Sophie Elena McGrath, Nicola Annels, Thumuluru K Madhuri, Anil Taylor, Simon A. Butler-Manuel, Richard Morgan, Hardev Pandha, Agnieszka Michael (2018)A novel Biomarker in epithelial ovarian cancer, In: BMC Cancer18943 BMC
BACKGROUND: Epithelial ovarian cancer is a common malignancy, with no clinically approved diagnostic biomarker. Engrailed-2 (EN2) is a homeodomain-containing transcription factor, essential during embryological neural development, which is dysregulated in several cancer types. We evaluated the expression of EN2 in Epithelial ovarian cancer, and reviewed its role as a biomarker. METHODS We evaluated 8 Epithelial ovarian cancer cell lines, along with >100 surgical specimens from the Royal Surrey County Hospital (2009-2014). In total, 108 tumours and 5 normal tissue specimens were collected. En2 mRNA was evaluated by semi-quantitative RT-PCR. Histological sub-type, and platinum-sensitive/-resistant status were compared. Protein expression was assessed in cell lines (immunofluorescence), and in >150 tumours (immunohistochemistry). RESULTS En2 mRNA expression was elevated in serous ovarian tumours compared with normal ovary (p<0.001), particularly in high-grade serous ovarian cancer (p<0.0001) and in platinum-resistant tumours (p=0.0232). Median Overall Survival and Progression-free Survival were reduced with high En2 expression (OS=28 vs 42 months, p=0.0329; PFS=8 vs 27 months; p=0.0004). Positive cytoplasmic EN2 staining was demonstrated in 78% of Epithelial ovarian cancers, with absence in normal ovary. EN2 positive high-grade serous ovarian cancer patients had a shorter PFS (10 vs 17.5 months; p=0.0103). CONCLUSION The EN2 transcription factor is a novel ovarian cancer biomarker. It demonstrates prognostic value, correlating with worse Overall Survival and Progression-free Survival. It is hoped that further work will validate its use as a biomarker, and provide insight into the role of EN2 in the development, progression and spread of ovarian cancer.
RA Adair, KJ Scott, S Fraser, F Errington-Mais, H Pandha, M Coffey, P Selby, GP Cook, R Vile, KJ Harrington, G Toogood, AA Melcher (2012)Cytotoxic and immune-mediated killing of human colorectal cancer by reovirus-loaded blood and liver mononuclear cells., In: Int J Cancer
Reovirus is a promising oncolytic virus, acting by both direct and immune-mediated mechanisms, although its potential may be limited by inactivation after systemic delivery. Our study addressed whether systemically delivered reovirus might be shielded from neutralising antibodies by cell carriage and whether virus-loaded blood or hepatic innate immune effector cells become activated to kill colorectal cancer cells metastatic to the liver in human systems. We found that reovirus was directly cytotoxic against tumour cells but not against fresh hepatocytes. Although direct tumour cell killing by neat virus was significantly reduced in the presence of neutralising serum, reovirus was protected when loaded onto peripheral blood mononuclear cells, which may carry virus after intravenous administration in patients. As well as handing off virus for direct oncolytic killing, natural killer (NK) cells within reovirus-treated blood mononuclear cells were stimulated to kill tumour targets, but not normal hepatocytes, in a Type I interferon-dependent manner. Similarly, NK cells within liver mononuclear cells became selectively cytotoxic towards tumour cells when activated by reovirus. Hence, intravenous reovirus may evade neutralisation by serum via binding to circulating mononuclear cells, and this blood cell carriage has the potential to investigate both direct and innate immune-mediated therapy against human colorectal or other cancers metastatic to the liver.
EJ Ilett, RJ Prestwich, T Kottke, F Errington, JM Thompson, KJ Harrington, HS Pandha, M Coffey, PJ Selby, RG Vile, AA Melcher (2009)Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite pre-existing anti-viral immunity, In: GENE THERAPY16(5)pp. 689-699 NATURE PUBLISHING GROUP
R Morgan, A Boxall, KJ Harrington, GR Simpson, C Gillett, A Michael, HS Pandha (2012)Targeting the HOX/PBX dimer in breast cancer., In: Breast Cancer Res Treat136(2)pp. 389-398 Springer
The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in a number of malignancies, including breast cancer. While relatively little is known about the roles that individual HOX genes play in cancer, it is however clear that these roles can be both contradictory, with some members acting as oncogenes and some as tumor suppressors, and also redundant, with several genes essentially having the same function. Here, we have attempted to address this complexity using the HXR9 peptide to target the interaction between HOX proteins and PBX, a second transcription factor that serves as a common co-factor for many HOX proteins. We show that HXR9 causes apoptosis in a number of breast cancer-derived cell lines and that sensitivity to HXR9 is directly related to the averaged expression of HOX genes HOXB1 through to HOXB9, providing a potential biomarker to predict the sensitivity of breast tumors to HXR9 or its derivatives. Measuring the expression of HOX genes HOXB1-HOXB9 in primary tumors revealed that a subset of tumors show highly elevated expression indicating that these might be potentially very sensitive to killing by HXR9. Furthermore, we show that while HXR9 blocks the oncogenic activity of HOX genes, it does not affect the known tumor-suppressor properties of a subset of HOX genes in breast cancer.
L Vidal, HS Pandha, TA Yap, CL White, K Twigger, RG Vile, A Melcher, M Coffey, KJ Harrington, JS DeBono (2008)A Phase I Study of Intravenous Oncolytic Reovirus Type 3 Dearing in Patients with Advanced Cancer, In: CLINICAL CANCER RESEARCH14(21)pp. 7127-7137 AMER ASSOC CANCER RESEARCH
RJ Prestwich, F Errington, LP Steele, EJ Ilett, RSM Morgan, KJ Harrington, HS Pandha, PJ Selby, RG Vile, AA Melcher (2009)Reciprocal Human Dendritic Cell-Natural Killer Cell Interactions Induce Antitumor Activity Following Tumor Cell Infection by Oncolytic Reovirus, In: JOURNAL OF IMMUNOLOGY183(7)pp. 4312-4321 AMER ASSOC IMMUNOLOGISTS
S Gogalic, U Sauer, S Doppler, A Heinzel, P Perco, A Lukas, Guy Simpson, Hardev Pandha, A Horvath, C Preininger (2017)Validation of a protein panel for the non-invasive detection of recurrent non-muscle invasive bladder cancer, In: Biomarkers22(7)pp. 674-681 Taylor & Francis
Context: About 50–70% of patients with non-muscle invasive bladder cancer (NMIBC) experience relapse of disease. Objective: To establish a panel of protein biomarkers incorporated in a multiplexed microarray (BCa chip) and a classifier for diagnosing recurrent NMIBC. Materials and methods: Urine samples from 45 patients were tested. Diagnostic performance was evaluated by receiver operating characteristic (ROC) analysis. Results: A multi biomarker panel (ECadh, IL8, MMP9, EN2, VEGF, past recurrences, BCG therapies and stage at diagnosis) was identified yielding an area under the curve of 0.96. Discussion and conclusion: This biomarker panel represents a potential diagnostic tool for noninvasive diagnosis of recurrent NMIBC.
Artitaya Lophatananon, Sarah Stewart-Brown, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch Garcia, David E Neal, Freddie C Hamdy, Jenny L Donovan, Graham G Giles, Liesel M Fitzgerald, Melissa C Southey, Paul Pharoah, Nora Pashayan, Henrik Gronberg, Fredrik Wiklund, Markus Aly, Janet L Stanford, Hermann Brenner, Aida K Dieffenbach, Volker Arndt, Jong Y Park, Hui-Yi Lin, Thomas Sellers, Chavdar Slavov, Radka Kaneva, Vanio Mitev, Jyotsna Batra, Amanda Spurdle, Judith A Clements, Johanna Schleutker, BØrge G Nordestgaard, Fredrik Wiklund, Ruth C Travis, Christopher A Haiman, Stephen N Thibodeau, Christiane Maier, Vogel Walther, William J Blot, Adam S Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hardev Pandha, Manuel R Teixeira, Margaret Cook, Koveela Govindasami, Michelle Guy, Daniel Leongamornlert, Emma J Sawyer, Rosemary Wilkinson, Angela Morgan, Cyril Fisher, Edward J Saunders, Malgorzata Tymrakiewicz, Naomi Livni, Steve Hazel, Tokhir Dadaev, Angela Cox, Anne George, Athene Lane, Gemma Marsden, Michael Davis, Paul Brown, John Pedersen, John L Hopper, Ami Karlsson, Carin Cavalli-Bjoerkman, Jan Adolfson, Jan-Erik Johansson, Michael Broms, Paer Stattin, Suzanne Kolb, Christa Stegmaier, Babu Zachariah, Hyun Park, James Haley, Julio Pow-Sang, Maria Rincon, Selina Radlein, Aleksandrina Vlahova, Atanaska Mitkova, Darina Kachakova, Elenko Popov, Svetlana Christova, Tihomir Dikov, Allison Eckert, Angus Collins, Glenn Wood, Greg Malone, Kimberly Alexander, Kris Kerr, Mary-Anne Kedda, Megan Turner, Pamela Saunders, Peter Heathcote, Srilakshmi Srinivasan, Tracy Omara, Trina Yeadon, Felicity Lose, Douglas Easton, Rosalind A Eeles, Kenneth Muir (2017)Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium, In: British Journal of Cancer117(5)pp. 734-743 Cancer Research UK / Nature Publishing Group
Background: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer.
Methods: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions.
Results: The results suggest that height is associated with high-grade prostate cancer risk. Men with height 4180cm are at a 22% increased risk as compared to men with height o173cm (OR 1.22, 95% CI 1.01–1.48). Genetic variants in the growth pathway gene showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as compared to lowest score group.
Conclusions: There was no evidence of gene-environment interaction between height and the selected candidate SNPs. Our findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures.
H Pandha, KD Sorensen, TF Orntoft, S Langley, S Hoyer, M Borre, R Morgan (2012)Urinary engrailed-2 (EN2) levels predict tumour volume in men undergoing radical prostatectomy for prostate cancer., In: BJU Int110(6 Pt B)pp. E287-E292 Wiley-Blackwell
What's known on the subject? and What does the study add? There are a lot of potential prostate cancer biomarkers being evaluated. All aim to improve on the sensitivity and specificity of PSA. EN2 was recently shown by our group to have better sensitivity and specificity than PSA. EN2 is a simple ELISA test and is not dependent on other parameters, even PSA, unlike all the other current biomarkers under evaluation. To date, no marker correlates with the amount of cancer present - the present study shows this positive correlation with EN2 in men undergoing prostatectomy. The potential utility of this work is that by knowing that the level of EN2 corresponds to the amount of cancer present, irrelevant of tumour grade and number of cancer foci, we can define an EN2 level corresponding to small cancers, which can then undergo surveillance. We are conducting a further study that is aimed at determining whether the levels of EN2 in urine can indicate 'significant' vs 'non-significant cancer' using the threshold of 0.5 mL cancer (after Epstein's work).
KJ Harrington, RG Vile, A Melcher, J Chester, HS Pandha (2010)Clinical trials with oncolytic reovirus: Moving beyond phase I into combinations with standard therapeutics, In: CYTOKINE & GROWTH FACTOR REVIEWS21(2-3)pp. 91-98 ELSEVIER SCI LTD
RJ Prestwich, F Errington, RM Diaz, HS Pandha, KJ Harrington, AA Melcher, RG Vile (2009)The Case of Oncolytic Viruses Versus the Immune System: Waiting on the Judgment of Solomon, In: HUMAN GENE THERAPY20(10)pp. 1119-1132 MARY ANN LIEBERT INC
J Tuan, H Pandha, C Corbishley, V Khoo (2012)Basaloid carcinoma of the prostate: A literature review with case report, In: Indian Journal of Urology28(3)pp. 322-324
Basal cell carcinoma of the prostate (BCP) is a neoplasm composed of prostatic basal cells. There are only a few publications outlining the diagnosis, treatment, prognosis and outcome for BCP. Traditionally surgery has been used but these tumors also respond to concomitant chemo-radiotherapy. Using a BCP case report treated with radical chemo-radiotherapy from a chemotherapy regimen used in anal cancers, we propose an alternative management to the traditional options of radical surgery and radical radiotherapy.
KJ Harrington, EM Karapanagiotou, V Roulstone, KR Twigger, CL White, L Vidal, D Beirne, R Prestwich, K Newbold, M Ahmed, K Thway, CM Nutting, M Coffey, D Harris, RG Vile, HS Pandha, JS DeBono, AA Melcher (2010)Two-Stage Phase I Dose-Escalation Study of Intratumoral Reovirus Type 3 Dearing and Palliative Radiotherapy in Patients with Advanced Cancers, In: CLINICAL CANCER RESEARCH16(11)pp. 3067-3077 AMER ASSOC CANCER RESEARCH
S Gray, S Metcalf, A Boxall, G Middleton, I Bagwan, H Pandha, R Morgan (2013)The chorio-allantoicmembrane (CAM) model for testing HOX gene antagonism in pancreatic cancer, In: CANCER RESEARCH73(8)
A Michael, E Politi, E Havranek, C Corbishley, L Karapanagiotou, C Anderson, K Relph, KN Syrigos, H Pandha (2007)Prognostic significance of erythropoietin expression in human renal cell carcinoma, In: BJU INTERNATIONAL100(2)pp. 291-294 BLACKWELL PUBLISHING
S Gray, HS Pandha, A Michael, G Middleton, R Morgan (2011)HOX genes in pancreatic development and cancer., In: JOP12(3)pp. 216-219
The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are subsequently re-expressed in many types of cancer. Some recent studies have shown that HOX genes may have key roles both in pancreatic development and in adult diseases of the pancreas, including cancer. In this review we consider recent advances in elucidating the role of HOX genes in these processes, how they may connect early developmental events to subsequent adult disease, and their potential both as diagnostic markers and therapeutic targets.
T Kottke, N Boisgerault, RM Diaz, O Donnelly, D Rommelfanger-Konkol, J Pulido, J Thompson, D Mukhopadhyay, R Kaspar, M Coffey, H Pandha, A Melcher, K Harrington, P Selby, R Vile (2013)Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence, In: NATURE MEDICINE19(12)pp. 1625-1631 NATURE PUBLISHING GROUP
M Hingorani, CL White, S Zaidi, HS Pandha, AA Melcher, SA Bhide, CM Nutting, KN Syrigos, RG Vile, G Vassaux, KJ Harrington (2010)Therapeutic Effect of Sodium Iodide Symporter Gene Therapy Combined With External Beam Radiotherapy and Targeted Drugs That Inhibit DNA Repair, In: MOLECULAR THERAPY18(9)pp. 1599-1605 NATURE PUBLISHING GROUP
A Michael, J Coward, A Brown, N Barber, H Pandha (2015)The Tolerability of Sunitinib in Elderly Patients with Metastatic Renal Cancer, In: CLINICAL ONCOLOGY27(6)pp. 371-372 ELSEVIER SCIENCE LONDON
SM Rudman, C Comins, D Mukherji, M Coffey, K Mettinger, A Protheroe, KJ Harrington, H Pandha, JF Spicer (2009)Results of a phase I study to evaluate the feasibility, safety, and biological effects of intravenous administration of wild-type reovirus with docetaxel to patients with advanced malignancies, In: JOURNAL OF CLINICAL ONCOLOGY27(15)
JIG Coward, ED Larbi, H Pandha, A Michael (2011)The effect of age on first-line sunitinib treatment in patients with renal cell carcinoma (RCC)., In: J Clin Oncol 29: 2011 (suppl; abstr e15096)
Background: Sunitinib is a first line treatment for majority of patients with metastatic RCC. The recommended dose of 50mg often results in a spectrum of serious side effects which subsequently lead to dose reduction and may have an impact on response rates. Methods: We conducted a retrospective analysis of 62 RCC patients from single institution treated with sunitinib between September 2007-May 2010. Patients were stratified according to age groups, into ≤ 70 year old (y.o.) and > 70 y.o. to compare tolerability, response rates and median survival. Results: All patients were evaluable for toxicity, 55 patients were evaluable for response. 38 (61.2%) were ≤ 70 y.o. and 24 (38.8%) were >70y.o. 2 patients (5%) of ≤70 and 5 (20%) of > 70y.o. were non-evaluable for response due to early treatment discontinuation. The response rate was 36% in ≤70y.o. and 21% in >70 y.o., stable disease (SD) was observed in 41% ≤70 y.o. vs 47% in the older age group and progressive disease PD:22% vs 31.5% respectively. 24 (38.7%) of patients required dose reductions after the first or second cycle- 12 (33%) in ≤70 vs 11 (59%) in >70 yrs old. A small number of patients presented with PS 2 and these were started on a reduced dose of 37.5mg: 3 (8%) in ≤70y.o. and 11 (58%) > 70y.o. Toxcities were comparable in both groups however grade 3 palmar-plantar erythema (PPE) and mucositis (18% vs 1.6% and 18 vs 8% respectively) were more prevalent in the younger cohort. Grade 3 diarrhoea and fatigue were more common in older patients (10% in >70y.o vs 1.6% in ≤70y.o. and 16% vs 9.6% respectively). Median survival was 23 months for both age groups. Conclusions: Elderly patients more commonly require dose reduction due to poor performance status and toxicity profile. The objective response rate is lower with the lower dose intensity however the rate of disease stabilisation is comparable in both groups. The lower dose of Sunitinib is well tolerated in the elderly and this regimen should be considered for older patients with poor performance status.
R Seth, AA Khan, TD Pencavel, MJ Wilkinson, JN Kyula, G Simpson, H Pandha, A Melcher, R Vile, PA Harris, KJ Harrington (2015)Adenovirally Delivered Enzyme Prodrug Therapy with Herpes Simplex Virus-Thymidine Kinase in Composite Tissue Free Flaps Shows Therapeutic Efficacy in Rat Models of Glioma, In: PLASTIC AND RECONSTRUCTIVE SURGERY135(2)pp. 475-487 LIPPINCOTT WILLIAMS & WILKINS
M Ismail, R Morgan, K Harrington, J Davies, H Pandha (2010)Immunoregulatory effects of freeze injured whole tumour cells on human dendritic cells using an in vitro cryotherapy model, In: CRYOBIOLOGY61(3)pp. 268-274 ACADEMIC PRESS INC ELSEVIER SCIENCE
V Alonso-Camino, K Rajani, T Kottke, D Rommelfanger-Konkol, S Zaidi, J Thompson, J Pulido, L Ilett, P Selby, H Pandha, A Melcher, K Harrington, R Diaz, R Vile (2014)The Profile of Tumor Antigens Which Can Be Targeted By Immunotherapy Depends Upon the Tumor's Anatomical Site, In: MOLECULAR THERAPY22pp. S200-S200
E Karapanagiotou, H Pandha, G Hall, J Chester, A Melcher, J De Bono, M Gore, C Nutting, K Harrington (2008)Phase I Trial of Oncolytic Reovirus (Reolysin) in Combination With Carboplatin/Paclitaxel in Patients With Advanced Solid Cancers, In: JOURNAL OF IMMUNOTHERAPY31(9)pp. 952-952
A Michael, L Plowright, A Boxall, A Bhatt, S Di Palma, C Parker, H Pandha (2010)Evaluation of EN2 as a urine-based biomarker for prostate cancer., In: J Clin Oncol 28, 2010 (suppl; abstr e15129)
Background: Prostate cancer is a leading cause of cancer related death in men but its diagnosis is still complicated by the lack of a highly predictive biochemical marker. Here we show that the transcription factor Engrailed-2 is secreted from prostate tumours in a highly specific manner and is present in the urine of men with prostate cancer. Methods: Urine was collected under standardised conditions from men with prostate cancer, or with non-cancerous conditions of the prostate such as benign prostatic hypertrophy, or men who were found to have no prostate abnormalities after saturation biopsy. Results: Engrailed-2 protein was detected in the untreated, unconcentrated urine of 62% of men with prostate cancer, but only 3% of men with no prostatic abnormalities (n=258, p<0.001). Conclusions: Thus Engrailed-2 is a potential diagnostic marker for prostate cancer.
Z Kelly, Carla Moller-Levet, S McGrath, S Butler-Manuel, Thumuluru Madhuri, Andrzej Kierzek, Hardev Pandha, Richard Morgan, Agnieszka Michael (2016)The prognostic significance of specific HOX gene expression patterns in ovarian cancer, In: International Journal of Cancer139(7)pp. 1608-1617 Wiley
OBJECTIVE: HOX genes are vital for all aspects of mammalian growth and differentiation, and their dysregulated expression is related to ovarian carcinogenesis. The aim of the current study was to establish the prognostic value of HOX dysregulation as well as its role in platinum resistance. The potential to target HOX proteins through the HOX/PBX interaction was also explored in the context of platinum resistance. METHODS: HOX gene expression was determined in ovarian cancer cell lines and primary EOCs, and compared to expression in normal ovarian epithelium and fallopian tube tissue samples. Statistical analysis included one way ANOVA and t-tests, using statistical software R and GraphPad. RESULTS: 30 of the 39 HOX genes were overexpressed in high grade serous EOC compared to normal tissue, most significant being HOXA3, A9, B13 and C10. We detected a molecular HOX gene-signature that predicted poor outcome: overexpression of HOXB4 and HOXB9 was identified in high grade serous cell lines after platinum resistance developed. Targeting the HOX/PBX dimer with the the HXR9 peptide enhanced the cytotoxicity of cisplatin in platinum-resistant ovarian cancer.CONCLUSIONS: HOX genes are highly dysregulated in ovarian cancer. High expression of HOXA13, B6, C13, D1 and D13 is predictive of poor clinical outcome. Targeting the HOX/PBX dimer in platinum–resistant cancer represents a new therapeutic option that should be further developed and tested in clinical trials.
E Karapanagiotou, HS Pandha, G Hall, J Chester, A Melcher, M Coffey, J de Bono, ME Gore, CM Nutting, KJ Harrington (2009)Phase I/II trial of oncolytic reovirus (Reolysin) in combination with carboplatin/paclitaxel in patients (pts) with advanced solid cancers, In: JOURNAL OF CLINICAL ONCOLOGY27(15)
E Killick, R Morgan, F Launchbury, NE Annels, E Bancroft, E Page, E Castro, Z Kote-Jarai, RA Eeles, HS Pandha (2012)Detecting prostate cancer in BRCA1 and BRCA2 mutation carriers: A role for EN2?, In: JOURNAL OF CLINICAL ONCOLOGY30(15)
A Michael, J Zylstra, H Pandha (2011)The sun study-a biobank of sequential blood samples from patients with prostate cancer, In: BRITISH JOURNAL OF SURGERY98pp. 50-50
E Binda, SM Perez, H Pandha, M Eberl, A Hayday (2010)Monitoring the immunological effects of bisphosphonates in different treatment scenarios, In: IMMUNOLOGY131pp. 117-117
JC Hu, RS Coffin, NJ Graham, N Groves, PJ Guest, KJ Harrington, ND James, CA Love, I McNeish, LC Medley, A Michael, CM Nutting, HS Pandha, CA Shorrock, J Simpson, J Steiner, NM Steven, D Wright, RC Coombes (2006)A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor, In: Clin Cancer Res12(22)pp. 6737-6747
PURPOSE: To conduct a phase I clinical trial with a second-generation oncolytic herpes simplex virus (HSV) expressing granulocyte macrophage colony-stimulating factor (Onco VEXGM-CSF) to determine the safety profile of the virus, look for evidence of biological activity, and identify a dosing schedule for later studies. EXPERIMENTAL DESIGN: The virus was administered by intratumoral injection in patients with cutaneous or s.c. deposits of breast, head and neck and gastrointestinal cancers, and malignant melanoma who had failed prior therapy. Thirteen patients were in a single-dose group, where doses of 10(6), 10(7), and 10(8) plaque-forming units (pfu)/mL were tested, and 17 patients were in a multidose group testing a number of dose regimens. RESULTS: The virus was generally well tolerated with local inflammation, erythema, and febrile responses being the main side effects. The local reaction to injection was dose limiting in HSV-seronegative patients at 10(7) pfu/mL. The multidosing phase thus tested seroconverting HSV-seronegative patients with 10(6) pfu/mL followed by multiple higher doses (up to 10(8) pfu/mL), which was well tolerated by all patients. Biological activity (virus replication, local reactions, granulocyte macrophage colony-stimulating factor expression, and HSV antigen-associated tumor necrosis), was observed. The duration of local reactions and virus replication suggested that dosing every 2 to 3 weeks was appropriate. Nineteen of 26 patient posttreatment biopsies contained residual tumor of which 14 showed tumor necrosis, which in some cases was extensive, or apoptosis. In all cases, areas of necrosis also strongly stained for HSV. The overall responses to treatment were that three patients had stable disease, six patients had tumors flattened (injected and/or uninjected lesions), and four patients showed inflammation of uninjected as well as the injected tumor, which, in nearly all cases, became inflamed. CONCLUSIONS: Onco VEXGM-CSF is well tolerated and can be safely administered using the multidosing protocol described. Evidence of an antitumor effect was seen.
RJ Prestwich, F Errington, EJ Ilett, RSM Morgan, KJ Scott, T Kottke, J Thompson, EE Morrison, KJ Harrington, HS Pandha, PJ Selby, RG Vile, AA Melcher (2008)Tumor Infection by Oncolytic Reovirus Primes Adaptive Antitumor Immunity, In: CLINICAL CANCER RESEARCH14(22)pp. 7358-7366 AMER ASSOC CANCER RESEARCH
S McGrath, NE Annels, TK Madhuri, B Haagsma, ED Larbi, HS Pandha, A Michael (2012)Engrailed protein: A cancer-specific marker in epithelial ovarian cancer, In: JOURNAL OF CLINICAL ONCOLOGY30(15)
M Ismail, R Morgan, J Davies, H Pandha (2009)INHIBITION OF THE AQUAPORIN WATER CHANNELS INCREASES THE SENSITIVITY OF PROSTATE CANCER CELLS TO FREEZING INJURY., In: JOURNAL OF UROLOGY181(4)pp. 185-185
AA Al Olama, Z Kote-Jarai, SI Berndt, DV Conti, F Schumacher, Y Han, S Benlloch, DJ Hazelett, Z Wang, E Saunders, D Leongamornlert, S Lindstrom, S Jugurnauth-Little, T Dadaev, M Tymrakiewicz, DO Stram, K Rand, P Wan, A Stram, X Sheng, LC Pooler, K Park, L Xia, J Tyrer, LN Kolonel, L Le Marchand, RN Hoover, MJ Machiela, M Yeager, L Burdette, CC Chung, A Hutchinson, K Yu, C Goh, M Ahmed, K Govindasami, M Guy, TLJ Tammela, A Auvinen, T Wahlfors, J Schleutker, T Visakorpi, KA Leinonen, J Xu, M Aly, J Donovan, RC Travis, TJ Key, A Siddiq, F Canzian, K-T Khaw, A Takahashi, M Kubo, P Pharoah, N Pashayan, M Weischer, BG Nordestgaard, SF Nielsen, P Klarskov, MA Roder, P Iversen, SN Thibodeau, SK McDonnell, DJ Schaid, JL Stanford, S Kolb, S Holt, B Knudsen, AH Coll, SM Gapstur, WR Diver, VL Stevens, C Maier, M Luedeke, K Herkommer, AE Rinckleb, SS Strom, C Pettaway, ED Yeboah, Y Tettey, RB Biritwum, AA Adjei, E Tay, A Truelove, S Niwa, AP Choklcalingam, L Cannon-Albright, C Cybulski, D Wokolorczyk, W Kluzniak, J Park, T Sellers, H-Y Lin, WB Isaacs, AW Partin, H Brenner, AK Dieffenbach, C Stegmaier, C Chen, EL Giovannucci, J Ma, M Stampfer, KL Penney, L Mucci, EM John, SA Ingles, RA Kittles, AB Murphy, H Pandha, A Michael, AM Kierzek, W Blot, LB Signorello, W Zheng, D Albanes, J Virtamo, S Weinstein, B Nemesure, J Carpten, C Leske, S-Y Wu, A Hennis, AS Kibel, BA Rybicki, C Neslund-Dudas, AW Hsing, L Chu, PJ Goodman, EA Klein, SL Zheng, J Batra, J Clements, A Spurdle, MR Teixeira, P Paulo, S Maia, C Slavov, R Kaneva, V Mitev, JS Witte, G Casey, EM Gillanders, D Seminara, E Riboli, FC Hamdy, GA Coetzee, Q Li, ML Freedman, DJ Hunter, K Muir, H Gronberg, DE Nea, M Southey, GG Giles, G Severi, MB Cook, H Nakagawa, F Wiklund, P Kraft, SJ Chanock, BE Henderson, DF Easton, RA Eeles, CA Haiman (2014)A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer, In: NATURE GENETICS46(10)pp. 1103-1109 NATURE PUBLISHING GROUP
Richard Morgan, L Plowright, KJ Harrington, Agnieszka Michael, Hardev Pandha (2010)Targeting HOX and PBX transcription factors in ovarian cancer, In: BMC CANCER10ARTN 8pp. ?-? BIOMED CENTRAL LTD
Hardev Pandha, Lucy Heinemann, Guy Simpson, A Melcher, R Prestwich, F Errington, M Coffey, KJ Harrington, Richard Morgan (2009)Synergistic Effects of Oncolytic Reovirus and Cisplatin Chemotherapy in Murine Malignant Melanoma, In: Clinical Cancer Research15(19)pp. 6158-6166 American Association for Cancer Research
M Ismail, S Bokaee, J Davies, KJ Harrington, H Pandha (2009)Inhibition of the aquaporin 3 water channel increases the sensitivity of prostate cancer cells to cryotherapy, In: BRITISH JOURNAL OF CANCER100(12)pp. 1889-1895 NATURE PUBLISHING GROUP
C Comins, J Spicer, A Protheroe, D Mukherji, M Coffey, B Thompson, K Harrington, H Pandha (2008)A Phase I Study to Evaluate Systemic Wild-type Reovirus (REOLYSIN)(R) in Combination With Docetaxel in Patients With Advanced Malignancies, In: JOURNAL OF IMMUNOTHERAPY31(9)pp. 951-951
EM Karapanagiotou, JD Chester, HS Pandha, GM Gill, MC Coffey, K Mettinger, KJ Harrington (2010)A phase I/II study of oncolytic reovirus plus carboplatin/paclitaxel in patients with advanced solid cancers with emphasis on squamous cell carcinoma of the head and neck(SCCHN), In: JOURNAL OF CLINICAL ONCOLOGY28(15) AMER SOC CLINICAL ONCOLOGY
A Roberts, M Serrano, P Vantourout, F Dieli, H Pandha, AC Hayday (2010)Expansion of autologous human V gamma 9V delta 2 T cells ex vivo: potential for adoptive T cell therapy of prostate cancer, In: IMMUNOLOGY131pp. 119-119
S Pandha, GR Simpson, A Horvath, RS Coffin, T Pencavel, K Harrington (2011)Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer (visualised by micro CT), In: BRITISH JOURNAL OF SURGERY98pp. 52-53
RF Gabitass, NE Annels, HS Pandha, AW Middleton (2010)Prevalence and prognostic significance of myeloid-derived suppressor cells and regulatory T cells in pancreatic and esophagogastric cancer, In: JOURNAL OF CLINICAL ONCOLOGY28(15) AMER SOC CLINICAL ONCOLOGY
JN Kyula, AA Khan, D Mansfield, EM Karapanagiotou, M Mclaughlin, V Roulstone, S Zaidi, T Pencavel, Y Touchefeu, R Seth, NG Chen, YA Yu, Q Zhang, AA Melcher, RG Vile, HS Pandha, M Ajaz, AA Szalay, KJ Harrington (2014)Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling, In: Oncogene33(13)pp. 1700-1712
Melanoma is an aggressive skin cancer that carries an extremely poor prognosis when local invasion, nodal spread or systemic metastasis has occurred. Recent advances in melanoma biology have revealed that RAS-RAF-MEK-ERK signaling has a pivotal role in governing disease progression and treatment resistance. Proof-of-concept clinical studies have shown that direct BRAF inhibition yields impressive responses in advanced disease but these are short-lived as treatment resistance rapidly emerges. Therefore, there is a pressing need to develop new targeted strategies for BRAF mutant melanoma. As such, oncolytic viruses represent a promising cancer-specific approach with significant activity in melanoma. This study investigated interactions between genetically-modified vaccinia virus (GLV-1h68) and radiotherapy in melanoma cell lines with BRAF mutant, Ras mutant or wild-type genotype. Preclinical studies revealed that GLV-1h68 combined with radiotherapy significantly increased cytotoxicity and apoptosis relative to either single agent in V600D BRAF/V600E mutant melanoma in vitro and in vivo. The mechanism of enhanced cytotoxicity with GLV-1h68/radiation (RT) was independent of viral replication and due to attenuation of JNK, p38 and ERK MAPK phosphorylation specifically in BRAF mutant cells. Further studies showed that JNK pathway inhibition sensitized BRAF mutant cells to GLV-1h68-mediated cell death, mimicking the effect of RT. GLV-1h68 infection activated MAPK signaling in V600D BRAF/V600E BRAF mutant cell lines and this was associated with TNF-α secretion which, in turn, provided a prosurvival signal. Combination GLV-1h68/RT (or GLV-1h68/JNK inhibition) caused abrogation of TNF-α secretion. These data provide a strong rationale for combining GLV-1h68 with irradiation inV600D/E BRAF mutant tumors. © 2014 Macmillan Publishers Limited.
A Gusev, H Shi, G Kichaev, M Pomerantz, F Li, HW Long, SA Ingles, RA Kittles, SS Strom, BA Rybicki, B Nemesure, WB Isaacs, W Zheng, CA Pettaway, ED Yeboah, Y Tettey, RB Biritwum, AA Adjei, E Tay, A Truelove, S Niwa, AP Chokkalingam, EM John, AB Murphy, LB Signorello, J Carpten, MC Leske, S-Y Wu, AJM Hennis, C Neslund-Dudas, AW Hsing, L Chu, PJ Goodman, EA Klein, JS Witte, G Casey, S Kaggwa, MB Cook, DO Stram, WJ Blot, RA Eeles, D Easton, Z Kote-Jarai, AA Al Olama, S Benlloch, K Muir, GG Giles, MC Southey, LM Fitzgerald, H Gronberg, F Wiklund, M Aly, BE Henderson, J Schleutker, T Wahlfors, TLJ Tammela, BG Nordestgaard, TJ Key, RC Travis, DE Neal, JL Donovan, FC Hamdy, P Pharoah, N Pashayan, K-T Khaw, JL Stanford, SN Thibodeau, SK McDonnell, DJ Schaid, C Maier, W Vogel, M Luedeke, K Herkommer, AS Kibel, C Cybulski, D Wokolorczyk, W Kluzniak, L Cannon-Albright, C Teerlink, H Brenner, AK Dieffenbach, V Arndt, JY Park, TA Sellers, H-Y Lin, C Slavov, R Kaneva, V Mitev, J Batra, A Spurdle, JA Clements, MR Teixeira, HS Pandha, A Michael, P Paulo, S Maia, A Kierzek, DV Conti, D Albanes, C Berg, SI Berndt, D Campa, ED Crawford, WR Diver, SM Gapstur, JM Gaziano, E Giovannucci, R Hoover, DJ Hunter, M Johansson, P Kraft, L Le Marchand, S Lindstrom, C Navarro, K Overvad, E Riboli, A Siddiq, VL Stevens, D Trichopoulos, P Vineis, M Yeager, G Trynka, S Raychaudhuri, FR Schumacher, AL Price, ML Freedman, CA Haiman, B Pasaniuc, M Cook, M Guy, K Govindasami, D Leongamornlert, EJ Sawyer, R Wilkinson, EJ Saunders, M Tymrakiewicz, T Dadaev, A Morgan, C Fischer, S Hazel, N Livni, A Lophatananon, J Pedersen, JL Hopper, J Adolfson, P Stattin, J-E Johansson, C Cavalli-Bjoerkman, A Karlsson, M Broms, A Auvinen, P Kujala, L Maeaettaenen, T Murtola, K Taari, M Weischer, SF Nielsen, P Klarskov, A Roder, P Iversen, H Wallinder, LB Signorello, WJ Blot, L Tillmans, S Riska, L Wang, A Rinckleb, J Lubiski, C Stegmaier, J Pow-Sang, H Park, S Radlein, M Rincon, J Haley, B Zachariah, D Kachakova, E Popov, A Mitkova, A Vlahova, T Dikov, S Christova, P Heathcote, G Wood, G Malone, K Saunders, A Eckert, T Yeadon, K Kerr, A Collins, M Turner, S Srinivasan, M-A Kedda, K Alexander, T Omara, H Wu, R Henrique, P Pinto, J Santos, J Barros-Silva (2016)Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation, In: Nature Communications7
Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
M Ismail, H Kevin, R Morgan, J Davies, H Pandha (2009)ENHANCING PROSTATE CANCER CRYOTHERAPY USING TUMOUR NECROSIS FACTOR RELATED APOPTOSIS-INDUCING LIGAND (TRAIL) SENSITISATION IN A NOVEL IN VITRO MODEL, In: JOURNAL OF UROLOGY181(4)pp. 189-190
T Brend, Z Kelly, M Ajaz, R Morgan, H Pandha, SC Short (2014)THERAPEUTIC POTENTIAL OF TARGETING HOX PROTEIN FUNCTION IN GLIOBLASTOMA, In: NEURO-ONCOLOGY16
Nicola E Annels, David Mansfield, Mehreen Arif, Carmen Ballesteros-Merino, Guy R Simpson, Mick Denyer, Sarbjinder S Sandhu, Alan Melcher, Kevin J Harrington, BronwYn Davies, Gough Au, Mark Grose, Izhar N Bagwan, Bernard A. Fox, Richard G Vile, Hugh Mostafid, Darren Shafren, Hardev Pandha (2019)Viral targeting of non-muscle invasive bladder cancer and priming of anti-tumour immunity following intravesical Coxsackievirus A21, In: Clinical Cancer Research American Association for Cancer Research
Purpose: The CANON (CAVATAK in NON-muscle invasive bladder cancer) study evaluated a novel ICAM-1-targeted immunotherapeutic-coxsackievirus A21 as a novel oncolytic agent against bladder cancer.
Experimental Design: Fifteen patients enrolled on this 'window of opportunity' phase 1 study, exposing primary bladder cancers to CAVATAK prior to surgery. The first nine patients received intravesical administration of monotherapy CAVATAK; in the second stage, six patients received CAVATAK with a sub-therapeutic dose of mitomycinC, known to enhance expression of ICAM-1 on bladder cancer cells. The primary endpoint was to determine patient safety and maximum tolerated dose. Secondary endpoints were evidence of viral replication, induction of inflammatory cytokines, anti-tumour activity and viral-induced changes in resected tissue.
Results: Clinical activity of CAVATAK was demonstrated by induction of tumour inflammation and haemorrhage following either single or multiple administrations of CAVATAK in multiple patients, and a complete resolution of tumour in one patient. Whether used alone or in combination with mitomycinC, CAVATAK caused marked inflammatory changes within NMIBC tissue biopsies by up-regulating interferon-inducible genes including both immune checkpoint-inhibitory genes (PD-L1 and LAG3) and Th1-associated chemokines as well as induction of the innate activator RIG-I, compared to bladder cancer tissue from untreated patients. No significant toxicities were reported in any patient, from either virus or combination therapy.
Conclusions: The acceptable safety profile of CAVATAK, proof of viral targeting, replication and tumour cell death together with the virus-mediated increases in "immunological heat" within the tumour microenvironment all indicate that CAVATAK may be potentially considered as a novel therapeutic for NMIBC.
MA Eisenberger, A-C Hardy-Bessard, L Mourey, PN Mainwaring, D Ford, JD Shapiro, J Carles, S Ng, T Gil, B Alekseev, S Ivanov, T Facchini, E Legouffe, O Apolikhin, HS Pandha, A Beeker, O Karyakin, W Zhang, M Chadjaa, JS De Bono (2012)Comparison of two doses of cabazitaxel plus prednisone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel (D)-containing regimen, In: JOURNAL OF CLINICAL ONCOLOGY30(15)
K Rajani, C Parrish, T Kottke, J Thompson, S Zaidi, L Ilett, KG Shim, R-M Diaz, H Pandha, K Harrington, M Coffey, A Melcher, R Vile (2016)Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune Responses, In: MOLECULAR THERAPY24(1)pp. 166-174 NATURE PUBLISHING GROUP
SE McGrath, A Michael, R Morgan, H Pandha (2015)EN2 in Prostate Cancer., In: Adv Clin Chem71pp. 47-76
Despite extensive efforts to identify a clinically useful diagnostic biomarker in prostate cancer, no new test has been approved by regulatory authorities. As a result, this unmet need has shifted to biomarkers that additionally indicate presence or absence of "significant" disease. EN2 is a homeodomain-containing transcription factor secreted by prostate cancer into the urine and can be detected by enzyme-linked immunoassay. EN2 may be an ideal biomarker because normal prostate tissue and benign prostatic hypertrophic cells do not secrete EN2. This review discusses the enormous potential of EN2 to address this unmet need and provide the urologist with a simple, inexpensive, and reliable prostate cancer biomarker.
L Steele, F Errington, R Prestwich, E Ilett, K Harrington, H Pandha, M Coffey, P Selby, R Vile, A Melcher (2011)Pro-inflammatory cytokine/chemokine production by reovirus treated melanoma cells is PKR/NF-kappa B mediated and supports innate and adaptive anti-tumour immune priming, In: MOLECULAR CANCER10ARTN 20 BIOMED CENTRAL LTD
V Roulstone, M Pedersen, J Kyula, D Mansfield, AA Khan, G McEntee, M Wilkinson, E Karapanagiotou, M Coffey, R Marais, A Jebar, F Errington-Mais, A Melcher, R Vile, H Pandha, M McLaughlin, KJ Harrington (2015)BRAF- and MEK-Targeted Small Molecule Inhibitors Exert Enhanced Antimelanoma Effects in Combination With Oncolytic Reovirus Through ER Stress, In: MOLECULAR THERAPY23(5)pp. 931-942 NATURE PUBLISHING GROUP
V Alonso-Camino, K Rajani, T Kottke, D Rommelfanger-Konkol, S Zaidi, J Thompson, J Pulido, E Ilett, O Donnelly, P Selby, H Pandha, A Melcher, K Harrington, RM Diaz, R Vile (2014)The Profile of Tumor Antigens Which Can be Targeted by Immunotherapy Depends Upon the Tumor's Anatomical Site, In: MOLECULAR THERAPY22(11)pp. 1936-1948 NATURE PUBLISHING GROUP
K Rajani, K Shim, C Parrish, L Ilett, T Kottke, J Pulido, J Thompson, H Pandha, K Harrington, A Melcher, F Errington, R Diaz, M Coffey, S Zaidi, R Vile (2015)Combination Therapy of Reovirus and PD-1 Blockade Effectively Establishes Tumor Control Via Innate and Adaptive Immune Responses, In: MOLECULAR THERAPY23pp. S30-S30
A Michael, C Riley,, S Bokaee, M Denyer, H Pandha, N Annels (2011)EN2: A candidate antigen for the development of targeted therapies in ovarian cancer., In: JCO(J Clin)
Background: Ovarian cancer remains the most lethal gynaecologic tumour in the Western world. Stimulation of the immune system to consolidate response to chemotherapy can potentially be beneficial however so far none of the vaccination strategies have offered survival advantage. Thus identifying and targeting clinically relevant antigens for immunotherapy continues to be an important research strategy. We have evaluated Engrailed-2 (EN2) as a potential target for vaccine strategy. EN2 is a homeodomain-containing transcription factor with a multifunctional role in neural development. There is evidence that over-expression of EN2 protein maybe linked to tumour development. Methods: Ovarian cancer cell lines were analysed by FACS for EN2 cell surface expression. EN2 expression in ovarian cancer tissue arrays were done by immunohistochemistry. A serum analysis (ELISA) was done to evaluate the presence of antibodies to EN2 in ovarian cancer patients and age-matched controls. A set of potentially immunogenic HLA-A2 restricted epitopes from the EN2 protein was identified using a computer algorithm SYFPEITHI. These peptides have been tested on HLA-A2 positive ovarian cancer patients’ PBMC using an in vitro culture method. The specificity of these T cell lines was analysed against T2 target cells loaded with or without EN2 peptides Results: Cell surface expression of EN2 was observed in ovarian cancer cell lines OVCAR3, OV90, CaOV-3, ES-2 and SKOV-3 of which ES-2 and SKOV3 showed strong expression. EN2 was also present in approximately 80% of ovarian cancer tissues whereas EN-2 expression was very low (<10%) or absent in normal tissues. Out of the 67 ovarian cancer patients 20.9% (14/67) had antibodies against EN2 compared to 2.4% (1/42) of age-matched female controls. 4 of the identified EN2 epitopes were able to generate peptide specific cytotoxic T lymphocytes in the ovarian cancer patients tested. Conclusions: The over-expression and immunogenicity of EN2 in ovarian cancer makes it a credible antigen to exploit as a novel target for ovarian cancer immunotherapy. ž
RF Gabitass, NE Annels, DD Stocken, HA Pandha, GW Middleton (2011)Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13., In: Cancer Immunol Immunother
We undertook a comprehensive analysis of circulating myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) in pancreatic, esophageal and gastric cancer patients and investigated whether MDSCs are an independent prognostic factor for survival. We evaluated a series of plasma cytokines and in particular re-evaluated the Th2 cytokine interleukin-13 (IL-13). Peripheral blood was collected from 131 cancer patients (46 pancreatic, 60 esophageal and 25 gastric) and 54 healthy controls. PBMC were harvested with subsequent flow cytometric analysis of MDSC (HLADR(-) Lin1(low/-) CD33(+) CD11b(+)) and Treg (CD4(+) CD25(+) CD127(low/-) FoxP3(+)) percentages. Plasma IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 (p70), IL-13, IL-17, G-CSF, IFN-γ, TNF-α and VEGF levels were analyzed by the Bio-Plex cytokine assay. Plasma arginase I levels were analyzed by ELISA. MDSCs and Tregs were statistically significantly elevated in pancreatic, esophageal and gastric cancer compared with controls, and MDSC numbers correlated with Treg levels. Increasing MDSC percentage was associated with increased risk of death, and in a multivariate analysis, MDSC level was an independent prognostic factor for survival. A unit increase in MDSC percentage was associated with a 22% increased risk of death (hazard ratio 1.22, 95% confidence interval 1.06-1.41). Arginase I levels were also statistically significantly elevated in upper gastrointestinal cancer patients compared with controls. There was Th2 skewing for cytokine production in all three diseases, and importantly there were significant elevations of the pivotal Th2 cytokine interleukin-13, an increase that correlated with MDSC levels.
A Samson, K Scott, D Taggart, E West, E Wilson, G Nuovo, S Thomson, R Corns, R Mathew, M Fuller, T Kottke, J Thompson, E Ilett, J Cockle, P van Hille, G Sivakumar, E Polson, S Turnbull, E Appleton, G Migneco, A Rose, M Coffey, D Beirne, F Collinson, C Ralph, D Anthoney, C Twelves, A Furness, S Quezada, H Wurdak, F Errington-Mais, Hardev Pandha, K Harrington, P Selby, R Vile, S Griffin, L Stead, S Short, A Melcher (2018)Intravenous Delivery of Oncolytic Reovirus to Brain Tumor Patients Immunologically Primes for Subsequent Checkpoint Blockade, In: Science Translational Medicine10(422)eaam7577 American Association for the Advancement of Science
Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death-ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation, would upregulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous (i.v.) administration will not deliver virus to this site. Here we show, in a window-of-opportunity clinical study, that i.v. infusion of oncolytic human Orthoreovirus (referred to herein as reovirus), leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma (HGG) and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus upregulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.
Victoria A. Jennings, Gina B. Scott, Ailsa M.S. Rose, Karen J. Scott, Gemma Migneco, Brian Keller, Katrina Reilly, Oliver Donnelly, Howard Peach, Donald Dewar, Kevin J. Harrington, Hardev Pandha, Adel Samson, Richard G. Vile, Alan A. Melcher, Fiona Errington-Mais (2019)Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition, In: Molecular Therapy Elsevier
A clinical oncolytic herpes simplex virus (HSV) encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), talimogene laherparepvec, causes regression of injected and non-injected melanoma lesions in patients and is now licensed for clinical use in advanced melanoma. To date, limited data are available regarding the mechanisms of human anti-tumor immune priming, an improved understanding of which could inform the development of future combination strategies with improved efficacy. This study addressed direct oncolysis and innate and adaptive human immune-mediated effects of a closely related HSV encoding GM-CSF (HSVGM-CSF) alone and in combination with histone deacetylase inhibition. We found that HSVGM-CSF supported activation of anti-melanoma immunity via monocyte-mediated type I interferon production, which activates NK cells, and viral maturation of immature dendritic cells (iDCs) into potent antigen-presenting cells for cytotoxic T lymphocyte (CTL) priming. Addition of the histone deacetylase inhibitor valproic acid (VPA) to HSVGM-CSF treatment of tumor cells increased viral replication, viral GM-CSF production, and oncolysis and augmented the development of anti-tumor immunity. Mechanistically, VPA increased expression of activating ligands for NK cell recognition and induced expression of tumor-associated antigens, supporting innate NK cell killing and CTL priming. These data support the clinical combination of talimogene laherparepvec with histone deacetylase inhibition to enhance oncolysis and anti-tumor immunity.
R Szulkin, R Karlsson, T Whitington, M Aly, H Gronberg, RA Eeles, DF Easton, Z Kote-Jarai, AA Al Olama, S Benlloch, K Muir, GG Giles, MC Southey, LM FitzGerald, BE Henderson, FR Schumacher, CA Haiman, C Sipeky, TLJ Tammela, BG Nordestgaard, TJ Key, RC Travis, DE Neal, JL Donovan, FC Hamdy, PDP Pharoah, N Pashayan, K-T Khaw, JL Stanford, SN Thibodeau, SK McDonnell, DJ Schaid, C Maier, W Vogel, M Luedeke, K Herkommer, AS Kibel, C Cybulski, J Lubinski, W Kluzniak, L Cannon-Albright, H Brenner, V Herrmann, B Holleczek, JY Park, TA Sellers, H-Y Lim, C Slavov, RP Kaneva, VI Mitev, A Spurdle, MR Teixeira, P Paulo, S Maia, H Pandha, A Michael, A Kierzek, J Batra, JA Clements, D Albanes, GL Andriole, SI Berndt, S Chanock, SM Gapstur, EL Giovannucci, DJ Hunter, P Kraft, L Le Marchand, J Ma, AM Mondul, KL Penney, MJ Stampfer, VL Stevens, SJ Weinstein, A Trichopoulou, BH Bueno-de-Mesquita, A Tjonneland, DG Cox, L Maehle, J Schleutker, S Lindstroem, F Wiklund (2015)Genome-Wide Association Study of Prostate Cancer-Specific Survival, In: CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION24(11)pp. 1796-1800 AMER ASSOC CANCER RESEARCH
MI Ismail, S Bokaee, N Annels, J Davies, H Pandha (2011)Predominance of CD8 T cell infiltration coincides with reciprocal reduction in regulatory T cells following prostate cryotherapy, In: BRITISH JOURNAL OF SURGERY98pp. 48-48
L Plowright, KJ Harrington, HS Pandha, R Morgan (2009)HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer), In: BRITISH JOURNAL OF CANCER100(3)pp. 470-475 NATURE PUBLISHING GROUP
S Javed, H Pandha, R Morgan, S Bott, C Eden, S Langley (2013)Urinary Engrailed-2 (EN2) levels and their correlation with tumour volume and pathological tumour stage in men undergoing radical prostatectomy for prostate cancer, In: BJU INTERNATIONAL111pp. 12-12
O Donnelly, R Vile, H Pandha, K Harrington, A Melcher (2012)The hitchhiker's guide to virotherapy., In: Oncotarget3(8)pp. 735-736
D Mansfield, T Pencavel, JN Kyula, S Zaidi, V Roulstone, K Thway, L Karapanagiotou, AA Khan, M McLaughlin, Y Touchefeu, R Seth, AA Melcher, RG Vile, HS Pandha, KJ Harrington (2012)Oncolytic Vaccinia virus and radiotherapy in head and neck cancer., In: Oral Oncol
OBJECTIVE: Oncolytic forms of attenuated Vaccinia virus are now in clinical development, assessing the compatibility of this novel treatment with radiotherapy may reveal exploitable synergistic relationships. MATERIALS AND METHODS: In vitro analyses of cell killing, cell cycle effects and caspase activation were carried out on HN3, HN5, CAL27, Detroit, SIHN5B, and PJ41 cells. In vivo studies of the virus and X-radiation were performed on H&N xenografts in CD1 nude mice. RESULTS: Cell killing in vitro was demonstrated to be dose- and time-dependent. Infection causes an increase in S-phase and sub-G1 cells. A dose dependent increase in active caspase-3 indicated induction of apoptosis. Xenografts injected with Vaccinia stabilised and frequently completely regressed. Combination with radiation generated additional cell death, induction of caspase activity and in vivo further improved long term regression rates. CONCLUSIONS: These data support continued exploration of this therapy combination and indicates potential for clinical trials in head and neck cancer.
J John, M Ismail, C Riley, J Askham, R Morgan, A Melcher, H Pandha (2010)Differential effects of Paclitaxel on dendritic cell function, In: BMC IMMUNOLOGY11ARTN 14 BIOMED CENTRAL LTD
K Twigger, L Vidal, CL White, JS De Bono, S Bhide, M Coffey, B Thompson, RG Vile, L Heinemann, HS Pandha, F Errington, AA Melcher, KJ Harrington (2008)Enhanced in vitro and in vivo cytotoxicity of combined reovirus and radiotherapy, In: CLINICAL CANCER RESEARCH14(3)pp. 912-923 AMER ASSOC CANCER RESEARCH
L Plowright, L Shears, H Pandha, R Morgan (2007)Disrupting the interaction between Hox and PBX causes apoptotic cell death and reduces in vivo proliferation of a non-small cell lung cancer model, In: MOLECULAR CANCER THERAPEUTICS6(12)pp. 3504S-3504S AMER ASSOC CANCER RESEARCH
ZL Kelly, Agnieszka Michael, S Butler-Manuel, Hardev Pandha, Richard Morgan (2011)HOX genes in ovarian cancer, In: Journal of Ovarian Research4(1) Springer
The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development. Here we review a number of recent studies showing that HOX genes are strongly expressed in ovarian cancer, and that in some cases the expression of specific HOX genes is sufficient to confer a particular identity and phenotype upon cancer cells. We also review the recent advances in elucidating the different functions of HOX genes in ovarian cancer. A literature search was performed using the search terms HOX genes (including specific HOX genes), ovarian cancer and oncogenesis. Articles were accessed through searches performed in ISI Web of Knowledge, PubMed and ScienceDirect. Taken together, these studies have shown that HOX genes play a role in the oncogenesis of ovarian cancer and function in the inhibition of apoptosis, DNA repair and enhanced cell motility. The function of HOX genes in ovarian cancer oncogenesis supports their potential role as prognostic and diagnostic markers, and as therapeutic targets in this disease.
Robert J Motzer, Alain Ravaud, Jean-Jacques Patard, Hardev Pandha, Daniel J George, Anup Patel, Yen-Hwa Chang, Bernard Escudier, Frede Donskov, Ahmed Magheli, Giacomo Carteni, Brigitte Laguerre, Piotr Tomczak, Jan Breza, Paola Gerletti, Mariajose Lechuga, Xun Lin, Michelle Casey, Lucile Serfass, Allan J Pantuck, Michael Staehler (2017)Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results, In: European Urology73(1)pp. 62-68 Elsevier
Background:
Adjuvant sunitinib significantly improved disease-free survival (DFS) versus placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence after nephrectomy (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59–0.98; p = 0.03).
Objective:To report the relationship between baseline factors and DFS, pattern of recurrence, and updated overall survival (OS). Design, setting, and participants: Data for 615 patients randomized to sunitinib (n = 309) or placebo (n = 306) in the S-TRAC trial. Outcome measurements and statistical analysis: Subgroup DFS analyses by baseline risk factors were conducted using a Cox proportional hazards model. Baseline risk factors included: modified University of California Los Angeles integrated staging system criteria, age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), weight, neutrophil-to-lymphocyte ratio (NLR), and Fuhrman grade.
Results and limitations:Of 615 patients, 97 and 122 in the sunitinib and placebo arms developed metastatic disease, with the most common sites of distant recurrence being lung (40 and 49), lymph node (21 and 26), and liver (11 and 14), respectively. A benefit of adjuvant sunitinib over placebo was observed across subgroups, including: higher risk (T3, no or undetermined nodal involvement, Fuhrman grade 2, ECOG PS 1, T4 and/or nodal involvement; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55–0.99; p = 0.04), NLR 3 (HR 0.72, 95% CI 0.54–0.95; p = 0.02), and Fuhrman grade 3/4 (HR 0.73, 95% CI 0.55– 0.98; p = 0.04). All subgroup analyses were exploratory, and no adjustments for multiplicity were made. Median OS was not reached in either arm (HR 0.92, 95% CI 0.66–1.28; p = 0.6); 67 and 74 patients died in the sunitinib and placebo arms, respectively.
Conclusions:A benefit of adjuvant sunitinib over placebo was observed across subgroups. The results are consistent with the primary analysis, which showed a benefit for adjuvant sunitinib in patients at high risk of recurrent RCC after nephrectomy.
Patient summary:Most subgroups of patients at high risk of recurrent renal cell carcinoma after nephrectomy experienced a clinical benefit with adjuvant sunitinib.
Trial registration:ClinicalTrials.gov NCT00375674.
R Morgan, HS Pandha Antagonism of HOX/PBX dimer formation blocks the in vivo proliferation of melanoma, In: Cancer Research67(12)pp. 5806-5813 American Association for Cancer Research
F Errington, L Steele, R Prestwich, KJ Harrington, HS Pandha, L Vidal, J de Bono, P Selby, M Coffey, R Vile, A Melcher (2008)Reovirus activates human dendritic cells to promote innate antitumor immunity, In: JOURNAL OF IMMUNOLOGY180(9)pp. 6018-6026 AMER ASSOC IMMUNOLOGISTS
F Errington, CL White, KR Twigger, A Rose, K Scott, L Steele, LJ Ilett, R Prestwich, HS Pandha, M Coffey, P Selby, R Vile, KJ Harrington, AA Melcher (2008)Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma, In: GENE THERAPY15(18)pp. 1257-1270 NATURE PUBLISHING GROUP
A Horvath, GR Simpson, RS Coffin, H Mostafid, H Pandha (2009)NOVEL INTRAVESICAL THERAPY FOR NON MUSCLE INVASIVE BLADDER CANCER: COMBINATION OF A FUSOGENIC GLYCOPROTEIN, PRO-DRUG ACTIVATION AND ONCOLYTIC HERPES SIMPLEX VIRUS, In: EUR UROL SUPPL8(4)pp. 196-196 ELSEVIER SCIENCE BV
C Comins, GR Simpson, K Relph, KJ Harrington, A Melcher, H Pandha (2013)Reoviral Therapy for Cancer: Strategies for Improving Antitumor Efficacy Using Radio- and Chemotherapypp. 185-198
Reovirus type 3 Dearing (Reolysin, Oncolytics Biotech) is a wild-type double-stranded RNA virus that is ubiquitous and nonpathogenic in humans. It has been shown to be oncolytic by its ability to replicate in transformed cells but not in normal cells. Reovirus has been shown to exert significant antitumor effects in both preclinical in vitro and in vivo studies. In addition, reovirus can activate both innate and adaptive antitumor response against human and murine tumors. However, despite antitumor activity, the responses to reovirus monotherapy in human trials have been modest and short-lived. As a result, a number of potential strategies for improving antitumor efficacy are currently being evaluated. This chapter describes the application of oncolytic reovirus as an anticancer agent, alone or in combination with conventional therapies such as radiotherapy and chemotherapeutics. It also summarizes current clinical trials on reovirus therapy. © 2014 Elsevier Inc. All rights reserved.
H Pandha, G Pawelec (2015)Immune checkpoint targeting as anti-cancer immunotherapy: promises, questions, challenges and the need for predictive biomarkers at ASCO 2015, In: CANCER IMMUNOLOGY IMMUNOTHERAPY64(9)pp. 1071-1074 SPRINGER
S Zaidi, M Blanchard, K Shim, E Ilett, K Rajani, C Parrish, N Boisgerault, T Kottke, J Thompson, E Celis, J Pulido, P Selby, H Pandha, A Melcher, K Harrington, R Vile (2015)Mutated BRAF Emerges as a Major Effector of Recurrence in a Murine melanoma Model After Treatment With Immunomodulatory Agents, In: MOLECULAR THERAPY23(5)pp. 845-856 NATURE PUBLISHING GROUP
M De Paoli, S Gogalic, U Sauer, C Preininger, HS Pandha, G Simpson, A Horvath, C Marquette (2016)Multi-platform biomarker discovery for bladder cancer recurrence diagnosis, In: Disease Markers4591910 Hindawi Publishing Corporation
Purpose. Nonmuscle invasive bladder cancer (BCa) has a high recurrence rate requiring lifelong surveillance. Urinary biomarkers are promising as simple alternatives to cystoscopy for the diagnosis of recurrent bladder cancer. However, no single marker can achieve the required accuracy. The purpose of this study was to select a multiparameter panel, comprising urinary biomarkers and clinical parameters, for BCa recurrence diagnosis. Experimental Design. Candidate biomarkers were measured in urine samples of BCa patients with recurrence and BCa patients without recurrence. A multiplatform strategy was used for marker quantification comprising a multiplexed microarray and an automated platform for ELISA analysis. A multivariate statistical analysis combined the results from both platforms with the collected clinical data. Results. The best performing combination of biomarkers and clinical parameters achieved an AUC value of 0.91, showing better performance than individual parameters. This panel comprises six biomarkers (cadherin-1, IL-8, ErbB2, IL-6, EN2, and VEGF-A) and three clinical parameters (number of past recurrences, number of BCG therapies, and stage at time of diagnosis). Conclusions. The multiparameter panel could be a useful noninvasive tool for BCa surveillance and potentially impact the clinical management of this disease. Validation of results in an independent cohort is warranted.
Shea P. Connell, Marcelino Yazbek-Hanna, Frank McCarthy, Rachel Hurst, Martyn Webb, Helen Curley, Helen Walker, Rob Mills, Richard Y. Ball, Martin G. Sanda, Kathryn L. Pellegrini, Dattatraya Patil, Antoinette S. Perry, Jack Schalken, Hardev Pandha, Hayley Whitaker, Nening Dennis, Christine Stuttle, Ian G. Mills, Ingrid Guldvik, Chris Parker, Daniel S. Brewer, Colin S. Cooper, Jeremy Clark, Bharati Bapat, Rob Bristow, Andreas Doll, Jeremy Clark, Colin Cooper, Hing Leung, Ian Mills, David Neal, Mireia Olivan, Hardev Pandha, Antoinette Perry, Chris Parker, Martin Sanda, Jack Schalken, Hayley Whitaker (2019)A four-group urine risk classifier for predicting outcomes in patients with prostate cancer, In: BJU International Wiley
Objectives
To develop a risk classifier using urine‐derived extracellular vesicle (EV)‐RNA capable of providing diagnostic information on disease status prior to biopsy, and prognostic information for men on active surveillance (AS).
Patients and Methods
Post‐digital rectal examination urine‐derived EV‐RNA expression profiles (n = 535, multiple centres) were interrogated with a curated NanoString panel. A LASSO‐based continuation ratio model was built to generate four prostate urine risk (PUR) signatures for predicting the probability of normal tissue (PUR‐1), D'Amico low‐risk (PUR‐2), intermediate‐risk (PUR‐3), and high‐risk (PUR‐4) prostate cancer. This model was applied to a test cohort (n = 177) for diagnostic evaluation, and to an AS sub‐cohort (n = 87) for prognostic evaluation.
Results
Each PUR signature was significantly associated with its corresponding clinical category (P ˂ 0.001). PUR‐4 status predicted the presence of clinically significant intermediate‐ or high‐risk disease (area under the curve = 0.77, 95% confidence interval [CI] 0.70–0.84). Application of PUR provided a net benefit over current clinical practice. In an AS sub‐cohort (n = 87), groups defined by PUR status and proportion of PUR‐4 had a significant association with time to progression (interquartile range hazard ratio [HR] 2.86, 95% CI 1.83–4.47; P ˂ 0.001). PUR‐4, when used continuously, dichotomized patient groups with differential progression rates of 10% and 60% 5 years after urine collection (HR 8.23, 95% CI 3.26–20.81; P ˂ 0.001).
Conclusion
Urine‐derived EV‐RNA can provide diagnostic information on aggressive prostate cancer prior to biopsy, and prognostic information for men on AS. PUR represents a new and versatile biomarker that could result in substantial alterations to current treatment of patients with prostate cancer.
RA Adair, V Roulstone, KJ Scott, R Morgan, GJ Nuovo, M Fuller, D Beirne, EJ West, VA Jennings, A Rose, J Kyula, S Fraser, R Dave, DA Anthoney, A Merrick, R Prestwich, A Aldouri, O Donnelly, H Pandha, M Coffey, P Selby, R Vile, G Toogood, K Harrington, AA Melcher (2012)Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients., In: Sci Transl Med4(138)pp. 138ra77-?
Oncolytic viruses, which preferentially lyse cancer cells and stimulate an antitumor immune response, represent a promising approach to the treatment of cancer. However, how they evade the antiviral immune response and their selective delivery to, and replication in, tumor over normal tissue has not been investigated in humans. Here, we treated patients with a single cycle of intravenous reovirus before planned surgery to resect colorectal cancer metastases in the liver. Tracking the viral genome in the circulation showed that reovirus could be detected in plasma and blood mononuclear, granulocyte, and platelet cell compartments after infusion. Despite the presence of neutralizing antibodies before viral infusion in all patients, replication-competent reovirus that retained cytotoxicity was recovered from blood cells but not plasma, suggesting that transport by cells could protect virus for potential delivery to tumors. Analysis of surgical specimens demonstrated greater, preferential expression of reovirus protein in malignant cells compared to either tumor stroma or surrounding normal liver tissue. There was evidence of viral factories within tumor, and recovery of replicating virus from tumor (but not normal liver) was achieved in all four patients from whom fresh tissue was available. Hence, reovirus could be protected from neutralizing antibodies after systemic administration by immune cell carriage, which delivered reovirus to tumor. These findings suggest new preclinical and clinical scheduling and treatment combination strategies to enhance in vivo immune evasion and effective intravenous delivery of oncolytic viruses to patients in vivo.
Tyler M Seibert, Chun Chieh Fan, Yunpeng Wang, Verena Zuber, Roshan Karunamuni, J Kellogg Parsons, Rosalind A Eeles, Douglas F Easton, ZSofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch Garcia, Kenneth Muir, Henrik Grönberg, Fredrik Wiklund, Markus Aly, Johanna Schleutker, Csilla Sipeky, Teuvo LJ Tammela, Børge G Nordestgaard, Sune F Nielsen, Maren Weischer, Rasmus Bisbjerg, M Andreas Røder, Peter Iversen, Tim J Key, Ruth C Travis, David E Neal, Jenny L Donovan, Freddie C Hamdy, Paul Pharoah, Nora Pashayan, Kay-Tee Khaw, Christiane Maier, Walther Vogel, Manuel Luedeke, Kathleen Herkommer, Adam S Kibel, Cezary Cybulski, Dominika Wokolorczyk, Wojciech Kluzniak, Lisa Cannon-Albright, Hermann Brenner, Katarina Cuk, Kai-Uwe Saum, Jong Y Park, Thomas A Sellers, Chavdar Slavov, Radka Kaneva, Vanio Mitev, Jyotsna Batra, Judith A Clements, Amanda Spurdle, Manuel R Teixeira, Paula Paulo, Sofia Maia, Hardev Pandha, Agnieszka Michael, Andrzej Kierzek, David S Karow, Ian G Mills, Ole A Andreassen, Anders M Dale (2018)Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts, In: BMJ360j5757pp. 1-7 BMJ Publishing Group
Objectives: Prostate-specific-antigen (PSA) screening resulted in reduced prostate cancer (PCa) mortality in a large clinical trial, but due to many false positives and overdiagnosis of indolent disease, many guidelines do not endorse universal screening and instead recommend an individualized decision based on each patient’s risk. We sought to develop and validate a genetic tool to predict age of aggressive PCa onset and to guide decisions of whom to screen and at what age. Design: Genotype, PCa status, and age were analyzed to select single-nucleotide polymorphisms (SNPs) associated with PCa diagnosis. These SNPs were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (i.e., not eligible for surveillance per NCCN Guidelines; any of: Gleason score ≥7, stage T3-T4, PSA ≥10, nodal metastasis, distant metastasis). The resulting polygenic hazard score (PHS) is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and screening PSA data. PHS was calculated for these men to test prediction of PCa-free survival. Setting: Multiple, international PRACTICAL consortium member institutions. Participants: All PRACTICAL consortium participants of European ancestry with known age, PCa status, and quality-assured iCOGS array genotype data. Development dataset comprised 31,747 men. Validation dataset comprised 6,411 men. Main outcome measures: PHS prediction of age of onset of aggressive PCa in validation set. Results: In the independent validation set, PHS calculated from 54 SNPs was a highly significant predictor of age at diagnosis of aggressive PCa (z=11.2, p<10-16). When men in the validation set with high PHS (>98th percentile) were compared to those with average PHS (30th-70th percentile), the hazard ratio for aggressive PCa was 2.9. Conclusions:Polygenic hazard scores give personalized genetic risk estimates that predict for age of onset of aggressive PCa.
R Szulkin, T Whitington, M Eklund, M Aly, RA Eeles, D Easton, Z Kote-Jarai, AA Al Olama, S Benlloch, K Muir, GG Giles, MC Southey, LM Fitzgerald, BE Henderson, F Schumacher, CA Haiman, J Schleutker, T Wahlfors, TLJ Tammela, BG Nordestgaard, TJ Key, RC Travis, DE Neal, JL Donovan, FC Hamdy, P Pharoah, N Pashayan, K-T Khaw, JL Stanford, SN Thibodeau, SK McDonnell, DJ Schaid, C Maier, W Vogel, M Luedeke, K Herkommer, AS Kibel, C Cybulski, J Lubinski, W Kluzniak, L Cannon-Albright, H Brenner, K Butterbach, C Stegmaier, JY Park, T Sellers, H-Y Lim, C Slavov, R Kaneva, V Mitev, J Batra, JA Clements, A Spurdle, MR Teixeira, P Paulo, S Maia, H Pandha, A Michael, A Kierzek, H Gronberg, F Wiklund (2015)Prediction of Individual Genetic Risk to Prostate Cancer Using a Polygenic Score, In: PROSTATE75(13)pp. 1467-1474 WILEY-BLACKWELL
A Jebar, E West, K Scott, S Thomson, R Corns, MC Coffey, A Rose, G Nuovo, M Ryan, F Errington-Mais, C Ralph, C Twelves, S Griffin, KJ Harrington, HS Pandha, O Donnely, PJ Selby, R Vile, S Short, A Melcher (2014)Oncolytic wild-type reovirus infection in brain tumors following intravenous administration in patients., In: JOURNAL OF CLINICAL ONCOLOGY32(15)
CL White, T Menghistu, KR Twigger, PF Searle, SA Bhide, RG Vile, AA Melcher, HS Pandha, KJ Harrington (2008)Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo, In: GENE THERAPY15(6)pp. 424-433 NATURE PUBLISHING GROUP
NJ Vogelzang, TM Beer, J Bartunkova, R Kuklk, K Miller, WK Oh, S Oudard, HS Pandha, AO Sartor, R Spisek, NG Borgstein, WR Gerritsen (2015)Autologous dendritic cell vaccination (DCVAC/PCa) added to docetaxel chemotherapy in a double-blind, randomized phase III trial (VIABLE) in men with advanced (mCRPC) prostate cancer., In: JOURNAL OF CLINICAL ONCOLOGY33(15)
A Ravaud, RJ Motzer, Hardev S. Pandha, DJ George, AJ Pantuck, A Patel, YH Chang, B Escudier, F Donskov, A Magheli, G Carteni, B Laguerre, P Tomczak, J Breza, P Gerletti, M Lechuga, X Lin, JF Martini, K Ramaswamy, M Casey, M Staehler, JJ Patard (2016)Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy, In: New England Journal of Medicine375pp. 2246-2254 Massachusetts Medical Society
BACKGROUND
Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy.
METHODS
In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety.
RESULTS
The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects.
CONCLUSIONS
Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674.)
RJ Prestwich, F Errington, KJ Harrington, HS Pandha, P Selby, A Melcher (2008)Oncolytic viruses: do they have a role in anti-cancer therapy?, In: Clin Med Oncol2pp. 83-96
Oncolytic viruses are replication competent, tumor selective and lyse cancer cells. Their potential for anti-cancer therapy is based upon the concept that selective intratumoral replication will produce a potent anti-tumor effect and possibly bystander or remote cell killing, whilst minimizing normal tissue toxicity. Viruses may be naturally oncolytic or be engineered for oncolytic activity, and possess a host of different mechanisms to provide tumor selectivity. Clinical use of live replicating viruses is associated with a unique set of safety issues. Clinical experience has so far provided evidence of limited efficacy and a favourable toxicity profile. The interaction with the host immune system is complex. An anti-viral immune response may limit efficacy by rapidly clearing the virus. However, virally-induced cell lysis releases tumor associated antigens in a 'dangerous' context, and limited evidence suggests that this can lead to the generation of a specific anti-tumor immune response. Combination therapy with chemotherapy or radiotherapy represents a promising avenue for ongoing translation of oncolytic viruses into clinical practice. Obstacles to therapy include highly effective non-specific host mechanisms to clear virus following systemic delivery, immune-mediated clearance, and intratumoral barriers limiting virus spread. A number of novel strategies are now under investigation to overcome these barriers. This review provides an overview of the potential role of oncolytic viruses, highlighting recent progress towards developing effective therapy and asks if they are a realistic therapeutic option at this stage.
A Jebar, M Bentham, F Errington-Mais, K Scott, A Peckham-Cooper, R Dave, G Toogood, D Swinson, C Ralph, A Anthoney, M Coffey, K Harrington, H Pandha, R Vile, P Selby, A Melcher, S Griffin (2014)Combined anti-viral and anti-tumour therapy for virus-associated liver cancer, In: HUMAN GENE THERAPY25(12)pp. A27-A27
EJ Ilett, M Barcena, F Errington-Mais, S Griffin, KJ Harrington, HS Pandha, M Coffey, PJ Selby, RWAL Limpens, M Mommaas, RC Hoeben, RG Vile, AA Melcher (2011)Internalization of Oncolytic Reovirus by Human Dendritic Cell Carriers Protects the Virus from Neutralization, In: CLINICAL CANCER RESEARCH17(9)pp. 2767-2776 AMER ASSOC CANCER RESEARCH
JS de Bono, JM Piulats, HS Pandha, DP Petrylak, F Saad, LMA Aparicio, SK Sandhu, P Fong, S Gillessen, GR Hudes, T Wang, J Scranton, MN Pollak (2014)Phase II Randomized Study of Figitumumab plus Docetaxel and Docetaxel Alone with Crossover for Metastatic Castration-Resistant Prostate Cancer, In: CLINICAL CANCER RESEARCH20(7)pp. 1925-1934 AMER ASSOC CANCER RESEARCH
Fang Zhao, Ekaterina Olkhov-Mitsel, Shivani Kamdar, Renu Jeyapala, Julia Garcia, Rachel Hurst, Marcelino Yazbek Hanna, Robert Mills, Alexandra V. Tuzova, Eve O’Reilly, Sarah Kelly, Colin Cooper, Daniel Brewer, Antoinette S. Perry, Jeremy Clark, Neil Fleshner, Bharati Bapat, Colin Cooper, Bharati Bapat, Rob Bristow, Chris Parker, Ian Mills, Hardev Pandha, Hayley Whitaker, David Neal, Mireia Olivan, Hing Leung, Antoinette Perry, Martin Sanda, Jack Schalken (2018)A urine-based DNA methylation assay, ProCUrE, to identify clinically significant prostate cancer, In: Clinical Epigenetics10147pp. 1-12
Background Prevention of unnecessary biopsies and overtreatment of indolent disease remains a challenge in the management of prostate cancer. Novel non-invasive tests that can identify clinically significant (intermediate-risk and high-risk) diseases are needed to improve risk stratification and monitoring of prostate cancer patients. Here, we investigated a panel of six DNA methylation biomarkers in urine samples collected post-digital rectal exam from patients undergoing prostate biopsy, for their utility to guide decision making for diagnostic biopsy and early detection of aggressive prostate cancer. Results We recruited 408 patients in risk categories ranging from benign to low-, intermediate-, and high-risk prostate cancer from three international cohorts. Patients were separated into 2/3 training and 1/3 validation cohorts. Methylation biomarkers were analyzed in post-digital rectal exam urinary sediment DNA by quantitative MethyLight assay and investigated for their association with any or aggressive prostate cancers. We developed a Prostate Cancer Urinary Epigenetic (ProCUrE) assay based on an optimal two-gene (HOXD3 and GSTP1) LASSO model, derived from methylation values in the training cohort, and assessed ProCUrE’s diagnostic and prognostic ability for prostate cancer in both the training and validation cohorts. ProCUrE demonstrated improved prostate cancer diagnosis and identification of patients with clinically significant disease in both the training and validation cohorts. Using three different risk stratification criteria (Gleason score, D’Amico criteria, and CAPRA score), we found that the positive predictive value for ProCUrE was higher (59.4–78%) than prostate specific antigen (PSA) (38.2–72.1%) for all risk category comparisons. ProCUrE also demonstrated additive value to PSA in identifying GS ≥ 7 PCa compared to PSA alone (DeLong’s test p = 0.039), as well as additive value to the PCPT risk calculator for identifying any PCa and GS ≥ 7 PCa (DeLong’s test p = 0.011 and 0.022, respectively). Conclusions ProCUrE is a promising non-invasive urinary methylation assay for the early detection and prognostication of prostate cancer. ProCUrE has the potential to supplement PSA testing to identify patients with clinically significant prostate cancer.
NE Annels, GR Simpson, M Denyer, SE McGrath, G Falgari, E Killick, R Eeles, J Stebbing, D Pchejetski, R Cutress, N Murray, A Michael, H Pandha (2014)Spontaneous antibodies against Engrailed-2 (EN2) protein in patients with prostate cancer, In: CLINICAL AND EXPERIMENTAL IMMUNOLOGY177(2)pp. 428-438 WILEY-BLACKWELL
© 2013 Springer-Verlag London. All rights are reserved.Prostate cancer can present at any stage of the disease and very frequently does not cause any symptoms at all. Most cancers arise in the periphery of the prostate gland and cause symptoms only when they have grown to compress the urethra or invade the sphincter [1]. In recent years, more and more of prostate cancer patients from the western hemisphere are diagnosed at an earlier stage due to rising prevalence of prostate-specific antigen (PSA) testing [2]. A study by Cooperberg et al. analyzed trends in clinical presentation in 2,078 men diagnosed between 1989 and 2001. The proportion of patients with low-risk tumor characteristics rose from 29.8 % in 1989-1992 to 45.3 % in 1999-2001 [3]. Studies based on the Department of Defense Center for Prostate Disease (CPDR) found downward migration at higher stage [3]. The percentage of patients presenting with locally advanced (T3 to T4) disease fell from 19.2 % in 1988 to 4.4 % in 1998; rates of metastatic disease at diagnosis likewise declined from 14.1 % in 1988 to 3.3 % in 1998.
Marco Matejcic, Edward J Saunders, Tokhir Dadaev, Mark N Brook, Kan Wang, Xin Sheng, Ali Amin Al Olama, Fredrick R Schumacher, Sue A Ingles, Koveela Govindasami, Sara Benlloch, Sonja I Berndt, Demetrius Albanes, Stella Koutros, Kenneth Muir, Victoria L Stevens, Susan M Gapstur, Catherine M Tangen, Jyotsna Batra, Judith Clements, Henrik Gronberg, Nora Pashayan, Johanna Schleutker, Alicja Wolk, Catharine West, Lorelei Mucci, Peter Kraft, Géraldine Cancel-Tassin, Karina D Sorensen, Lovise Maehle, Eli M Grindedal, Sara S Strom, David E Neal, Freddie C Hamdy, Jenny L Donovan, Ruth C Travis, Robert J Hamilton, Barry Rosenstein, Yong-Jie Lu, Graham G Giles, Adam S Kibel, Ana Vega, Jeanette T Bensen, Manolis Kogevinas, Kathryn L Penney, Jong Y Park, Janet L Stanford, Cezary Cybulski, Børge G Nordestgaard, Hermann Brenner, Christiane Maier, Jeri Kim, Manuel R Teixeira, Susan L Neuhausen, Kim De Ruyck, Azad Razack, Lisa F Newcomb, Davor Lessel, Radka Kaneva, Nawaid Usmani, Frank Claessens, Paul A Townsend, Manuela G Dominguez, Monique J Roobol, Florence Menegaux, Kay-Tee Khaw, Lisa A Cannon-Albright, Hardev Pandha, Stephen N Thibodeau, Daniel J Schaid, Fredrik Wiklund, Stephen J Chanock, Douglas F Easton, Rosalind A Eeles, Zsofia Kote-Jarai, David V Conti, Christopher A Haiman (2018)Germline variation at 8q24 and prostate cancer risk in men of European ancestry, In: Nature Communications94616 Nature Research
Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p<4.28x10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI=3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.