Characterisation of a novel series of small molecule androgen receptor modulators in prostate cancer

Prostate cancer causes approximately 10,000 deaths in the UK each year. Current treatments attempt to prevent the action of the androgen receptor, a protein that drives prostate cancer growth. Unfortunately, these treatments are not effective in the long-term and the generation of disease that no longer responds to this therapy, termed hormone-refractory prostate cancer (HRPC), is common and often fatal. Therefore, the key goal for researchers is to develop new drugs that can be used to treat this disease.

The androgen receptor remains an important driving force in the development of HRPC and therefore the generation of new agents that can permanently block it?s function are necessary to effectively treat the disease.

This project will study the effect of a new panel of drugs that can inactivate the androgen receptor in several model systems of HRPC. These studies will provide important information regarding the effect of these agents on androgen receptor action and growth of prostate cancer cells. Ultimately, this work will be important for determining the effectiveness of these drugs as future therapies for prostate cancer treatment.

Prostate cancer (CaP) causes approximately 10,000 deaths per year in the UK alone. Current treatments for the disease attempt to inactivate the androgen receptor (AR), a member of the nuclear hormone receptor family of transcription factors, that regulates genes involved in prostate growth and transformation. Initial response to androgen-ablation therapy is good, but in most cases, the cancer recurs in a more aggressive form that is no longer responsive to hormonal therapy and is termed hormone-refractory prostate cancer (HRPC). There is a requirement therefore to develop new treatments that are effective against HRPC.

The fact that the AR is expressed and functional in HRPC, and is important for tumour expansion, indicates that the receptor remains a prominent target for therapy. Therefore, attenuating the function of the AR via distinct, non-conventional mechanisms in HRPC by novel receptor modulators is one avenue of research that requires attention.

AstraZeneca have identified a series of novel compounds that reduce AR activity in vivo as demonstrated by attenuation of testosterone stimulated growth of sexual accessory organs in both immature weanling rats and in mature castrated rats. Importantly, preliminary studies in vitro and in vivo indicate that the mechanism of repression is distinct from currently used adjuvant therapies and may lead to efficacy in HRPC. Further characterisation of these compounds is therefore vital for translation into the clinical setting.

To this end, we plan to perform the following experiments:

i. The effect of these novel AR modulators on transcriptional activity and cellular movement of the receptor will be assessed using a panel of CaP cell line models that mimic androgen-dependent and HRPC disease. We will also assess receptor turnover in response to compound treatment and identify enzymes responsible for driving modulator activity.

ii. The efficacy of the novel agents will be assessed in vivo using either subcutaneous xenograft or hollow fibre models of HRPC, incorporating androgen-insensitive cell lines. Tumour growth and proliferation will be determined and ex vivo analysis of disease markers will be performed by immunohistochemistry.

Ultimately, this study will characterise the efficacy of these novel AR modulators in both in vitro and in vivo models that will be a major step towards the generation of a new and much needed treatment for HRPC.