Targeting the androgen receptor in castration-resistant prostate cancer


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Gerhardt Attard
The Institute of Cancer Research, London, UK

Abstract

The survival benefit demonstrated with the CYP17A1 inhibitor abiraterone and the novel anti-androgen MDV3100 have confirmed the critical role played by androgen receptor (AR) signalling in a significant proportion of prostate cancer patients progressing despite castrate levels of androgens and after several lines of hormone treatment and taxane chemotherapy. A rising PSA at progression in the majority of patients and tumour responses, albeit less frequent, to further hormone manipulations suggest that a significant number of abiraterone- and MDV3100-resistant cancers remain driven by the AR. Evaluation of alternative therapeutic strategies for targeting the AR are therefore warranted. Ligands that could activate wild-type or mutant AR persist in patients treated with abiraterone and we hypothesise could cause resistance. Similarly, it was recently shown that androgen levels rise >10 fold in patients treated with MDV3100 and in vitro we have demonstrated increasing androgen levels out-competing MDV3100 from the AR, with reactivation of AR signalling. These observations support the development of CYP17A1 inhibitor-AR antagonist combination strategies. Several novel AR antagonists are also currently in Phase I/II development. Additionally, strategies for LBD-independent targeting of AR are in late preclinical/early clinical development, including HSP90 inhibitors and small molecule inhibitors and peptidomimetics targeting the AR amino-terminal domain. Combination targeting of AR and "cross-talk" pathways, including the PI3K-AKT pathway, that when activated could drive targets of AR, also merit evaluation.

The development of novel AR targeting drugs, combined with an increasing number of effective therapeutics for CRPC, urgently requires predictive biomarkers that could allow selection of patients for one treatment in preference to another. My talk will discuss novel therapeutic strategies for targeting AR and biomarker assays for CRPC patient selection.