Novel therapeutic strategies for castrate resistant prostate cancer
Research into the identification of molecular/cellular mechanisms that lead to the development of castrate resistant prostate cancer (CRPC). In particular the development of therapeutic strategies to inhibit the oncogenic transcription factor the Androgen Receptor (AR) which is the major driver of the disease with an overall goal to eradicate CRPC or delay its onset.
Viral therapy of cancer
In recent years viruses have been widely investigated in scientific research for their use as novel therapies for disease. We are investigating both herpes simplex virus (HSV) and reovirus in bladder and prostate models.
Reovirus is able to replicate within tumour cells and not in normal healthy cells of the body due to a specific mutation of a gene common to many cancers. As the virus replicates within the tumour cells new viral offspring are produced. These burst out of the cell causing the tumour cell to burst and die. We are studying the ability of reovirus to kill a variety of tumour cell types and, more specifically, the ability of reovirus to work in conjunction with conventional chemotherapy and also immunotherapy in prostate and bladder tumour cells.
Immunotherapy for cancer
We are interested in the immune microenvironment of tumours and in particular how we can make immunotherapy more effective by manipulating immune cells within it. Prostate cancers are generally considered to be a ‘cold’ tumour with minimal T cell infiltrates, lack of a type I IFN signature and chemokines and containing immunosuppressive cells such as myeloid derived suppressor cells. This non-inflamed phenotype is thought to be largely responsible for the disappointing lack of sensitivity of prostate cancer patients to immune checkpoint blockade (ICB) therapy. However, the use of oncolytic viruses can overcome pre-existing mechanisms of resistance to ICB in prostate cancers by transforming these cold tumours into ‘hot’, immune cell infiltrated, tumours. Such biological therapy can be further enhanced with the use of relevant immune checkpoint blockade that can overcome any constitutive or compensatory inhibitory resistance mechanisms.
We have used reovirus in combination with ICB to treat subcutaneous prostate tumours to try to understand at what stage of prostate cancer such an immunotherapy would be most effective. Having determined at what stage of the disease is most ‘cold’/noninflamed, strategies to optimally invigorate an immune response using oncolytic viruses with or without the immunomodulatory prostate cancer agent enzalutamide are being tested. Any immunologic changes, e.g. expression of immune checkpoints, that occur in the tumour microenvironment in response to OV treatment at particular disease stages will be identified and targeted. We hypothesize that designing such novel reovirus and immunotherapy combinations that specifically target the relevant inhibitory immune profile of a stage-specific prostate cancer will lead to enhanced treatment effects for more patients presenting with tumours throughout the spectrum of prostate cancer.
Embryonic gene targeting
Potential targets for novel therapies include proteins involved in cell growth and signalling within the cell. These include proteins, so called transcription factors, that have previously been identified as being switched on in cancer and therefore lead to unchecked growth of cells. Of particular note are the HOX genes, a family of proteins normally involved in development of the nervous system in the embryo.
We have designed a small protein, HXR9, which is able to pass into the cell and disrupt the interaction between HOX and a second protein, PBX. This protein is able to cause cell death when added to cancer cells in culture and can also reduce or prevent the growth of melanoma, breast, lung, ovarian and prostate tumours. We are developing this protein further for use as a therapy for cancer.
Engrailed 2 (EN2) - a potential urine biomarker in Prostate Cancer
PSA is an important and useful test for prostate cancer. However, its use is limited by the fact that PSA levels also increase in non-cancerous conditions of the prostate.
We have discovered that the EN2 protein is highly expressed in prostate cancer and that prostate cancer cells export EN2 into urine. Importantly, the amount of EN2 in urine can provide information about how large a tumour is. We have published our work in the journals Clinical Cancer Research and British Journal of urology, and we have received widespread publicity in the media. Work is ongoing to improve the accuracy of the test and address its potential in diagnosis and surveillance.
Urinary engrailed-2 (EN2) levels predict tumour volume in men undergoing radical prostatectomy for prostate cancer. Pandha H, Sorensen KD, Orntoft TF, Langley S, Hoyer S, Borre M, Morgan R. BJU Int. 2012 Sep;110(6 Pt B):E287-92
Engrailed-2 (EN2): A Tumor Specific Urinary Biomarker for the Early Diagnosis of Prostate Cancer. Morgan R, Boxall A, Bhatt A, Bailey M, Hindley R, Langley S, Whitaker HC, Neal DE, Ismail M, Whitaker H, Annels N, Michael A, Pandha H. Clin Cancer Res. 2011 Mar 1;17(5):1090-8
The Sun Study
- Complete a bio-repository and accompanying ‘database’ of 300 patients with all stages of prostate cancer to allow longitudinal blood sampling whilst on different treatment programs, and enable banking and analysis of serum and DNA at 6 monthly intervals. This group is unique in that it comprises an almost homogenous population of Caucasian patients, most of who won’t move out of the area (allowing long term follow up).
- Using the SUN study population, we will identify proteins in the blood serum which are characteristic for prostate cancer in comparison with benign disease (those patients found not to harbour cancer after prostatic biopsy, will be aged matched controls), using sophisticated cutting edge methods of protein analysis.
- We will identify changes in biomarker profile depending on the cancer stage and cancer grade in newly diagnosed cancer following radical treatment, in patients on hormonal treatment, in patients with hormone – resistant disease and in patients with widespread disease.
- We are currently setting up an ethnic Sun Study to look at the differences in biomarkers between the afro-caribean population, who have a very high incidence of prostate cancer, and the caucasian population.
This resource is available to researchers internationally and we are pleased to announce that we are now members of National Cancer Research Institute’s Confederation of Cancer Biobanks (CCB). CCB is a consortium of organisations based in the UK that are involved in the development, management and use of biobank resources for cancer research. Please contact Dr Agnieszka Michael for further details.