PROJECT SUMMARY / ABSTRACT The androgen receptor (AR) is the central determinant of prostate tissue identity and differentiation, controlling normal, growth-suppressive gene expression associated with differentiation of prostate cells. It is also a key driver of prostate tumorigenesis, becoming “hijacked” to drive oncogenic transcription. However, the key factors that mediate this switch, and whether the growth suppressive program can be reactivated to inhibit prostate cancer, remain unknown. Critically, AR also remains the key therapeutic target for prostate cancer, even in advanced, treatment resistant disease, where genomic alterations such as massive amplification, overexpression, mutations, and splice variants of AR drive continued reliance on androgen signaling. Therefore, understanding how AR is reprogrammed from its normal growth suppressive role to an oncogenic factor has major impact on our understanding of context-specific regulation of lineage-specific transcription factors and responses to prostate cancer therapies targeting AR. Our work has shown, in both published and unpublished preliminary data, that specific factors mediate the balance of AR activity between normal and oncogenic transcriptional programs. In unpublished preliminary data, we use a novel system to modulate canonical androgen receptor response element (ARE) motifs to show that the normal AR transcriptional program is governed by AREs, and reactivation of this normal program is growth suppressive in prostate cancer cells. We hypothesize that the growth-suppressive AR transcriptional program can be reactivated in advanced prostate cancer, and specific genomic and epigenetic modulators will mediate the transition between normal and oncogenic AR activity. We will test this hypothesis with three Specific Aims: 1) Determine the context that allows engagement of growth suppressive AR transcriptional programs in prostate cancer, 2) Establish the translational implications of oncogenic and growth suppressive AR programs in human prostate cancer patients, and 3) Define the key cofactors and modifiers that mediate the switch between normal and oncogenic AR programs. With a combination of novel epigenomic modulation strategies, functional genomics, genetically engineered mouse models, patient derived model systems, and human patient data, we will establish the potential of reactivating the AR growth suppressive program in vitro and in vivo, examine the implications for patients, and define novel AR cofactors and therapeutic targets. Together, these studies will evaluate an innovative, potentially transformative treatment strategy for lethal prostate cancer, expose new biology and new therapeutic targets, and define a new paradigm for cancers dependent on lineage-specific, multifunctional transcription factors.

NARRATIVE The androgen receptor (AR) defines and controls gene expression that is growth suppressive in the normal prostate, but in prostate cancer cells, AR is converted to driving cancer-promoting gene expression. This project will define the factors that mediate this switch, and explore the possibility of reactivating the normal, growth suppressive AR gene expression programs in advanced prostate cancers, thereby halting progression. These studies will evaluate an innovative, potentially transformative treatment strategy for lethal prostate cancer, expose new biology and new therapeutic targets, and define a new paradigm for cancers dependent on lineage-specific, multifunctional transcription factors.