Professor Hardev Pandha


Professor of Medical Oncology
+44 (0)1483 688602
26 PGM 02

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Ground-breaking cancer study - call for participants | Surrey Research Bites

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Publications

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
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.

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)
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
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.

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.

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
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.

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)
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
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
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.

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
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.

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
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
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
A Michael, H Pandha (2013)Presentation and symptomatology of prostate cancerpp. 467-471

© 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.

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
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
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
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
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.

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
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
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
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
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.

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
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
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.

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.

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
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.

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.

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
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)
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
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.

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.

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
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
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.)

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
L Plowright, K Harrington, HS Pandha, R Morgan (2017)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.

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
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
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.

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
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
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.

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
Roshan Karunamuni, Minh-Phuong Huynh-Le, Chun C. Fan, Rosalind A. Eeles, D Easton, Zsofia Kote-Jarai, A Amin Al Olama, Sara Benlloch Garcia, Kenneth Muir, Henrik Grönberg, Fredrik Wiklund, M Aly, Johanna Schleutker, Csilla Sipeky, Teuvo L. J. Tammela, Børge G. Nordestgaard, Tim J. Key, Ruth C Travis, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, P Pharoah, Nora Pashayan, K-T Khaw, SN Thibodeau, SK McDonnell, DJ Schaid, Christiane Maier, W Vogel, M Luedeke, K Herkommer, Adam S. Kibel, Cezary Cybulski, Dominika Wokolorczyk, W Kluzniak, L Cannon-Albright, Hermann Brenner, Ben Schöttker, Bernd Holleczek, Jong Y Park, T Sellers, Hui-Yi Lin, C Slavov, Radka Kaneva, V Mitev, Jyotsna Batra, JA Clements, A Spurdle, Manuel R. Teixeira, P Paulo, S Maia, HARDEV SINGH PANDHA, AGNIESZKA MICHAEL, Ian G. Mills, Ole A Andreassen, Anders M. Dale, Tyler M Seibert (2020)The effect of sample size on polygenic hazard models for prostate cancer, In: European journal of human genetics : EJHG28(10)pp. 1467-1475 Springer International Publishing

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR 98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69–1.77] to 2.41 [2.40–2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR 98/50 of the Discovery-SNP model increased from 1.05 [0.93–1.18] to 2.19 [2.16–2.23]. HR 98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70–1.85] and 1.73 [1.71–1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

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
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
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
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
Z Kelly, H Pandha, K Madhuri, R Morgan, A Michael (2012)HOX GENE EXPRESSION IN OVARIAN CANCER, In: ANNALS OF ONCOLOGY23pp. 68-68
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.

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.

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
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
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

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
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
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.