Focus Area: Therapy: Identification of new targets, pathways, and therapeutic modalities.

Androgen receptor (AR) signaling is a prominent player in the lethal progression of localized prostate cancer to the castration resistant (CRPC) stage. Recently, a second generation of anti-androgen, Enzalutamide or MDV3100 (marketed as Xtandi), has been introduced for the treatment of CRPC patients. Enzalutamide inhibits AR function by interfering with its translocation to the nucleus. Although highly effective, as seen by significant decrease in serum PSA (prostate specific antigen) levels, Enzalutamide provided palliative benefits only in a subset of CRPC patients. Moreover, the overall survival advantage appears to be modest (4-6 months), and even the most responding patients relapsed within ~2 years. One mechanism that has not been explored so far is the role of oncogenic tyrosine kinases in phosphorylating AR and their role in Enzalutamide resistance. Notably, some of these oncogenic kinases confer both androgen independence and anti-androgen resistance to prostate cancer cells -- an underlying basis for their pathological links to hormone refractory and metastatic prostate cancers. The hypothesis is that CRPCs could endow "super-penetrance" to AR via camouflaging it with post-translational phosphorylation marks. This proposal will use an innovative affinity-based method to uncover novel molecular targets mediating Enzalutamide resistance. Results from this project will provide novel insights into the mechanisms conferring Enzalutamide resistance. Moreover, it will also uncover the possibility wherein small molecule tyrosine kinase inhibitors could be utilized as a new therapeutic option for Enzalutamide-resistant CRPC patients.