Therapeutic Targeting of Chromatin Modifiers in Advanced Prostate Cancer

Abstract

Prostate cancer is the second-most common cancer in North American men. Although early intervention can successfully treat prostate cancer, there are limited option for advanced stages of the disease, and 1 in 30 men will ultimately die from this disease. Thus, it is critical to identify new targets and new models for therapeutic intervention, including treatments that do not target androgen signaling. The enzyme Ezh2 is one of the most highly-expressed genes in advanced prostate cancer, and has been shown to be a key driver of lethal metastatic prostate cancer. Ezh2 is the enzymatic component of the Polycomb Repressive Complex 2 (PRC2), which maintains transcriptional silencing of genes through methylation of lysine 27 on histone H3. The goal of this thesis has been to develop an effective Ezh2-inhibitor based combination therapy for advanced prostate cancer. Specifically, I have been examining the effects of combining Ezh2 inhibitors with agents that target histone deacetylases (HDACs), an additional type of chromatin-modifying enzyme. HDACs also function in transcriptional repression complexes and remove acetyl groups (a marker of gene activation) from histones. Based on the precise mechanism by which Ezh2 and HDACs function, my hypothesis was that these agents might cooperatively de-repress key genes and kill these advanced prostate cancers. I found that EZH2 and HDAC inhibitors potently cooperate in vitro and in vivo and cause dramatic tumor regression in CRPC models. Interestingly, this cytotoxic effect is dependent on the transcription factor ATF3, a stress integrator which triggers apoptosis in the presence of excessive levels of stress. ATF3 is normally suppressed by the PRC2 complex and becomes potently upregulated only in the presence of combined Ezh2 and HDAC inhibitors. These findings suggest that Ezh2 and HDAC suppression of ATF3 may serve as an important protective mechanism that is engaged during tumor evolution. Moreover, these studies have identified a new promising therapeutic for these currently untreatable malignancies.