A novel targetable mechanism for castration-resistant prostate cancer

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Project Summary Prostate cancer is the most frequently diagnosed cancer among veteran cancer patients with more than 13,000 veterans diagnosed with prostate cancer each year. Castration-resistant prostate cancer (CRPC) is a lethal type of prostate cancer due to developing resistance to androgen deprivation therapy and the new generation of anti-androgen drugs (i.e. Abiraterone Acetate, and Enzalutamide). Therefore, there is an urgent need to develop novel approaches for treatment of CRPC by understanding mechanisms leading to CRPC and identifying new therapeutic targets. Aberrant Wnt/β-catenin signaling plays a critical role in resistance to anti-androgen therapies and in CRPC. In our preliminary studies, we found that Slit/Robo GTPase activating protein 1 (srGAP1) is a potential Wnt target gene and co-regulated by androgen receptor (AR) signaling in CRPC. In addition, we found that multiple components of Slit/Roundabout (Robo) signaling, including srGAP1, Robo1, Slit2 and RhoA, are amplified and overexpressed in CRPC compared to primary PCa. Vice versa, Slit/Robo signaling can activate Wnt/β-catenin signaling by promoting the nuclear localization of β-catenin via Rac1 activation. We have also discovered that srGAP1 interacts with guanine nucleotide exchange factor (GEF) family of oncogenes Vav2/Vav3 that are known to regulate nuclear levels of androgen receptor variant 7 (AR V7 and full-length AR) and the survival of CRPC cells. Based these observations, we hypothesize that srGAP1 plays a critical role in progression to CRPC through reciprocal amplification of both AR and Wnt signaling. To test these hypotheses, we will first test the hypothesis that srGAP1 is one of the required down- stream intermediates for progression to CRPC and for resistance to anti-androgen therapies. Second, we will assess the functional and mechanistic importance of srGAP1 on AR and Wnt/-catenin signaling and on biological behaviors of CRPC. Third, we will determine pathophysiological relevance of the interplay between Slit/Robo/srGAP1, AR and Wnt signaling and whether the expression of srGAP1 will be a good predictor for disease progression and overall survival of CRPC patients. We expect to define the role and mechanisms of srGAP1 in progression to CRPC, which may lead to identification of a novel target or prognostic markers for the management of this deadly neoplasm. Therefore, our proposed work aligns very well with priority research areas of the Department of VA---Diseases with a high healthcare burden in the Veteran population and Precision medicine studies focused on individual treatment response.