Prostate cancer (PCa) is a leading cause of morbidity and mortality in the United States, and contributes to a significant healthcare burden due to an overall lack of curative interventions for advanced-stage disease. Because PCa is largely insensitive to cytotoxic chemotherapy, the androgen receptor (AR) has long been the primary therapeutic target for the clinical management of locally advanced and metastatic PCa. Problematically, targeting AR signaling via androgen deprivation or treatment with AR antagonists is associated with progression to lethal, castration-resistant prostate cancer (CRPC) via a variety of molecular mechanisms that alter AR expression and function. However, CRPC is marked by a continued reliance on AR expression and activity. Thus, new modes of intervention with ability to durably repress AR activity in advanced CRPC are an unmet clinical need. In Chapter 1, we review the problem of castration resistance through a new paradigm of genetic rearrangements that produce truncated AR variants (ARV), which confer resistance to all current forms of AR-based PCa therapy. In Chapter 2, we discuss a novel AR inhibitor that directly targets the AR NH2-terminal transcriptional activation domain (NTD), but with significant off-target effects due to the lack of specificity for the intrinsically disordered NTD. In Chapter 3, we characterize the differences in NTD utilization between full length AR and ARV. Finally, in Chapter 4, we discuss a brief history of AR targeting in PCa, and offer a perspective on how future translational studies can approach the problem of intrinsic disorder in the NTD to develop new interventions with more durable and lasting mechanisms of action.
University of Minnesota Ph.D. dissertation. April 2015. Major: Microbiology, Immunology and Cancer Biology. Advisor: Scott Dehm. 1 computer file (PDF); xi, 140 pages.
Therapeutic Targeting of Intrinsically Disordered Androgen Recptor Functional Domains in Prostate Cancer.
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