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Epigenetic Machinery Regulates Alternative Splicing of Androgen Receptor (AR) Gene in Castration-Resistant Prostate Cancer

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UT Southwestern Medical Center Dallas United States

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Androgen receptor pathway inhibition ARPI is the primary treatment for metastatic prostate cancer PCa since PCa depends on androgen for growth. Although initially responsive, most tumors progress into androgen-independentcastration-resistant PCa CRPC. No curative therapy is available. One of the ways for PCa cell to evade targeted therapy is the emergence of constitutively active AR variants AR-Vs such as AR-V7 that does not depend on androgen. Our research goal is to test the hypothesis that the epigenetic regulator KDM4B, a histone lysine demethylase, promotes AR-V7 via alternative splicing, leading to CPRC. We have made significant progress in the last year on identification of the mechanism by which KDM4B regulates AR-V7 and establishing the efficacy of our newly identified KDM4B inhibitor B3 as a monotherapy or combined with approved anti-androgen agents in AR-V7-expressing CRPC in preclinical mouse models.

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Technical Report,01 Sep 2017,31 Aug 2018



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Approved For Public Release;

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