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.