Project 4: Small molecule inhibitors of histone demethylases in prostate cancer

The standard androgen deprivation therapies involving either chemical or surgical castration for androgen-dependent prostate cancer (ADPC), although effective at the beginning, can lead to inevitable castration-resistant prostate cancer (CPRC), which is lethal to patients. The growth of both ADPC and CRPC depends on androgen receptor (AR)-signaling.

AR is a transcription factor and turns on many genes that promote cancer cell growth and proliferation. AR does not act alone. It needs other accomplices to turn on gene transcription. Two classes of enzymes called histone demethylases that remove methyl groups from histones are required for AR-dependent gene transcription.

In collaboration with Drs. HongTao Yu, Jose Rizo-Rey, and Jer-Tong Hsieh (UT Southwestern), and Dr. Jung-Mo Ahn (UT Dallas) we obtained the CPRIT multi-investigator research award. We plan to study how the two classes of histone demethylases (LSD1 and JMJDs) work together with AR to turn on growth-promoting genes. We have developed several small molecule inhibitors of enzymatic activities of LSD1 and JMJD2, and peptide mimetics that disrupt the binding of AR to its co-factors.

We will test whether these compounds kill prostate cancer cells in culture dishes and in mice. We will optimize our current drugs to improve their bioactivity and will develop additional drugs based on the studies proposed here. This project will define new molecular targets for treating prostate cancer and will lay the foundation for the development of new drugs that may be effective in treating prostate cancer and overcome castration-resistance.