Predicting response and resistance to AR-axis inhibition in castration resistant prostate cancer

Elahe Mostaghel, MD, PhD, Fred Hutchinson Cancer Research Center

Castration resistant prostate cancer (CRPC) is variably characterized by elevated tissue androgens, expression of steroidogenic enzymes capable of mediating androgen biosynthesis, persistent to elevated androgen receptor (AR), and the recently described expression of constitutively active AR splice variants. The extent to which therapeutic efficacy of agents targeting the AR axis is unknown.

Hypothesis: We hypothesize that differences in androgen levels, the steroidogenic transcriptome and androgen receptor/splice variant expression underlie tumor-specific differences in response and resistance to agents targeting the AR axis in CRPC. We hypothesize that baseline differences in these parameters can be used to determine optimal treatment regimens.

Aim 1. Establish the ‘castration recurrent profile’, including tumor androgens, steroidogenic enzyme expression and AR/variant levels in a panel of LuCaP xenografts spanning a range of baseline differences in these parameters.

Aim 2. Determine whether response and mechanisms of resistance to the AR pathway inhibitors VN-124, dutasteride and MDV3100 correspond to those predicted by tumor-specific differences in AR axis parameters.

If successful, this proposal will provide a strong impetus to determine the ability (and feasibility) of tissue biopsy or CTC-based methods of tumor sampling to yield real-time pre-treatment data profiles. Importantly, our data indicate that individual CRPC tumors appear to maintain a tumor-specific, functionally relevant and identifiable AR and steroidogenic transcriptome, suggesting that valid data indicative of inherent steroidogenic potential and treatment response can be obtained via in situ sampling of human tumor metastases.