Androgen Receptor Regulation by Microtubule‐targeting Chemotherapeutics in Prostate Cancer

Prostate cancer (PCa) is the 2 nd leading cause of cancer related death in N. American males and progression to androgen independence is associated with patient mortality. Castration‐resistant prostate cancer (CRPC) is a consequence of lack of apoptotic response to androgen‐ablation therapy (ADT) and chemotherapy, and the most critical therapeutic endpoint for PCa patients is defying this resistance. The basis for therapeutic failure to ADT is androgen independent activation of AR driving uncontrolled tumor growth. Taxane‐based chemotherapy is the only clinically effective treatment for CRPC via stabilization of microtubules resulting in apoptosis. Recent evidence identified the contribution of microtubules to AR signaling and consequences of their inhibition by taxanes on AR activity in PCa. Human PCa tumors exhibited decreased nuclear AR localization after taxol treatment versus untreated. Impairing AR activity enables a targeting platform for taxane‐based chemotherapy during PCa progression and supports a combination strategy toward an improved therapeutic response. AR variants capable of ligand independent signal may be critical in dictating taxane response. Ongoing work pursues the mechanism of taxane resistance driven by distinct AR variant activity in CRPC. Department of Defense Synergistic Idea Development Award