The androgen receptor (AR) is the master transcription factor responsible for development and maintenance of the male phenotype. Hyperactive AR signaling caused by AR gene amplification or coactivator overexpression is a hallmark of metastatic prostate cancer, which remains a major health burden in South Texas. Drugs that inhibit AR by outcompeting its steroid ligands have been used since the 1940s; however, resistance to these therapeutics inevitably arises through rebounds in AR signaling or alternative pathways that render tumors AR-independent. Development of more effective therapies that target AR’s oncogenic function requires a robust in vitro system that faithfully recapitulates AR ac...

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The androgen receptor (AR) is the master transcription factor responsible for development and maintenance of the male phenotype. Hyperactive AR signaling caused by AR gene amplification or coactivator overexpression is a hallmark of metastatic prostate cancer, which remains a major health burden in South Texas. Drugs that inhibit AR by outcompeting its steroid ligands have been used since the 1940s; however, resistance to these therapeutics inevitably arises through rebounds in AR signaling or alternative pathways that render tumors AR-independent. Development of more effective therapies that target AR’s oncogenic function requires a robust in vitro system that faithfully recapitulates AR activity and its response to oncoprotein coactivators. I have devised the first recombinant system to isolate active, full-length AR that enables rigorous biochemical and structural analyses of AR and its oncoprotein cofactors. As a CPRIT-supported investigator, my research program will employ a combinatorial approach of structural biology and biochemistry to tackle salient questions pertaining to AR regulation, from intramolecular contacts that fine-tune its activity, to cofactor interactions that allow AR to activate an oncogenic transcriptome. In Goal 1, I will utilize biochemical reconstitution, single particle cryo-electron microscopy, X-ray crystallography, and atomic force microscopy to elucidate the molecular details underlying AR hyperactivation and determine the functional consequences of these interactions in prostate model systems including genetically engineered organoids and AR-dependent cancer cell lines. In Goal 2, I will leverage my structural and biochemical findings and collaborations with the CPRIT-funded Center for Innovative Drug Discovery and institutional colleagues to discover and derive novel inhibitors that work by ablating AR protein or impairing AR function through disruption of AR/cofactor interactions.

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