UT Southwestern Medical Center Dallas United States
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.