Mechanisms of Androgen Receptor Inverse Agonists in Advanced Prostate Cancer

ABSTRACT Nuclear receptors are steroid-dependent transcription factors that confer cell identity and function. They guide development, and maintain homeostasis in adult tissue, such as the testosterone responsive Androgen Receptor which governs male-specific organs and phenotypes. Aberrant AR-driven gene expression programs

give rise to prostate cancer. When resistance arises after androgen-deprivation therapy (ADT) the disease advances to the much more lethal metastatic castration-resistant prostate cancer (mCRPC), often becoming resistant to ADT by overexpressing AR. New evidence suggests that many other transcription factors and

epigenetic co-activator proteins may create disease-specific enhancers with the AR to drive tumors, especially in treatment-relapsed mCRPC. By harnessing sophisticated molecular biology and computational biology techniques, we will map the epigenetic mechanisms at work in mCRPC, in clinically relevant PDX models and

cell lines with epigenomes closely matching mCRPC tumors. We will show how to stop the AR-axis using small molecules (AR in verse agonists, ARIAs) we designed, synthesized and developed with novel mechanisms of action, where the AR undergoes a chemically induced functional switch, causing the AR to suppress the tumor-

driving genes it normally activates. We will study the way AR creates super clusters in the diseased genome, and how our new therapy works by altering the co-regulators recruited to AR-super clusters. At the conclusion of this work, we should have mechanistic understanding the AR under the influence of an inverse agonist,

provide functional 3D epigenetic map of regulatory addictions in advanced PCa, and have explored therapeutic potential of promising new AR therapeutics.