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Dynamics of Epigenetic Mechanisms in the Akt Signaling Pathway and Its Influences on Drug Response in Advanced Prostate Cancer


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Objective: Preliminary data shows that AKT inhibition (AKTi) is associated with significant anti-tumor effect in multiple models of advanced PCa, which is enhanced when combined with AR targeted therapy. This correlates with increase in expression of some canonically AR-regulated genes, with a prolonged timeline consistent with epigenetic regulation, and with epigenetic changes over the same timeline. This project seeks to characterize how AKTi alters the AR cistrome and identify the mechanism through which this occurs. My approach is to characterize AR cistrome alterations and the broader epigenetic effects combined with a candidate gene approach to test my hypothesis that regulation of KMT2D by AKT mediates the epigenetic effects. Impact: This project is expected to greatly enhance our understanding of the role of the PI3K/AKT pathway in PCa progression, its interaction with AR activity, and its effect on epigenetic modifications. While this pathway has long been a focus of PCa research, there is renewed interest because of encouraging preliminary clinical results with AKT inhibition. After PARP inhibitors, AKT inhibitors are potentially the next targeted therapy approved for PCa. This study will improve our understanding of the biological effects of this class of drugs and help optimize the use of these drugs in the clinic. At the completion of the proposed projects, results will address the overarching challenges of developing effective treatments that improve outcomes for men with lethal PCa.



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