Enhancing the Efficacy of Androgen Signaling Inhibitors in Prostate Cancer

It has been documented that androgen receptor (AR) signaling remains to play a critical role in castration-resistant prostate cancer (CRPC). Indeed, Androgen Signaling Inhibitors (ASI), such as abiraterone, an inhibitor of de novo androgen synthesis pathway, and enzalutamide, a direct AR inhibitor, are major drugs used in clinic to manage CRPC now. Unfortunately, ASI-based treatment only improves the overall patient survival by several months. Therefore, understanding the underlying mechanisms of ASI resistance and development of novel avenues to increase the efficacy of ASI-based therapy are urgently needed. With the goal to identify new pathways/targets whose inhibition might overcome ASI resistance, we performed extensive bioinformatics analyses of RNA-seq data including those from paired prostate cancer (PCa) cells with different sensitivities to enzalutamide, 498 PCa tumors with different responses to hormone therapy and 52 pairs of PCa specimen (tumors vs adjacent normal). Both the ƒÒ-catenin-dependent canonical Wnt cascade and the ƒÒ-catenin-independent non-canonical Wnt signaling were identified as pathways whose elevation might contribute to acquisition of ASI resistance. The objective of the proposed research is to define the roles of Wnt signaling in acquisition of ASI resistance in CRPC and to exploit these pathways as novel therapeutic targets for CRPC patients who no longer respond to ASIs. The central hypothesis is that Wnt signaling causes constitutive activation of AR signaling, thus CRPC progression and development of ASI resistance. This hypothesis will be tested by pursuing three Specific Aims - (1) to dissect the role ofƒnƒÒ-catenin signaling in enzalutamide resistance of PCa; (2) to examine how activation of the non-canonical Wnt signaling contributes to enzalutamide resistance in PCa; and (3) to test whether simultaneous inhibition of canonical and non-canonical Wnt cascades is an effective approach to treat enzalutamide-resistant PCa and to probe the significance of tumor microenvironment Wnt in the acquisition of enzalutamide resistance. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing gain-of-function and loss-of-function strategies with inducible PCa mouse models, culture systems, human PCa xenograft, and patient-derived organoid methodologies. The rationale for the research is that it will be the first to comprenhensively probe the importance of Wnt signaling in acquisition of ASI resistance of CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Wnt signaling activates AR; (ii) genetically evaluate how these pathways contribute to PCa progression and metastasis; and (iii) demonstrate Wnt cascades as critical therapeutic targets to enhance the efficacy of ASI