Epigenetic Machinery Regulates Alternative Splicing of Androgen Receptor (AR) Gene in Castration Resistant Prostate Cancer
Technical Report,01 Sep 2016,31 Aug 2017
UT Southwestern Medical Center Dallas United States
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Androgen deprivation therapy ADT 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 reasons for the resistance to ADT and newer anti-androgen drugs is the emergence of constitutively active AR variants AR-Vs such as AR-V7 that are induced under ADT conditions. 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. A multi-disciplinary approach including molecular biology, tumor biology, cell biology, and biochemical method is used to test this hypothesis. In collaboration with a partnering principal investigator we are also testing the efficacy of our newly identified KDM4B inhibitors as a monotherapy or combined with approved anti-androgen agents in AR-V7-expressing CRPC in preclinical mouse models.
- Medicine and Medical Research