Targeting EZH2 in Castration-Resistant Prostate Cancer
Abstract
Scientific Rationale, Objectives and Aims: Metastatic castration-resistant prostate cancer (CRPC) is a major cause of prostate cancer-associated mortality. Genes/proteins that drive or sustain CRPC tumor growth and metastasis are promising targets for therapeutic intervention. EZH2 (enhancer of zest 2), an enzyme that catalyzes histone 3 lysine 27 trimethylation (H3K27me3), was found as one of the most upregulated genes in CRPC in 2002. For over a decade, studies have shown that EZH2 expression is critical for prostate cancer cell proliferation, invasion, as well as xenograft tumor growth and metastasis in mice models, which strongly supports EZH2 as a promising therapeutic target in CRPC and has propelled the development of EZH2 inhibitors that aim to suppress its enzymatic activity. Ironically, enzymatic EZH2 inhibitors such as EPZ-6438 (also called Tazemetostat, Epizyme) are currently in multiple clinical trials in other cancer types, with limited efficacy in prostate cancer. Emerging evidence suggests that EZH2 may play non-catalytic roles in prostate cancer cells, the understanding of which will be essential to effective EZH2-targeting in CRPC. Addressing this pressing need, our preliminary data suggest the androgen receptor (AR) as a critical target and mediator of the non-catalytic roles of EZH2. We found that EZH2 can directly induce the transcription of the AR gene. Importantly, this newly identified function is independent of the catalytic role of EZH2, as the enzymatically inactivate mutant EZH2-H689A remains capable of inducing AR expression. Further, enzymatic EZH2 inhibitor failed to block AR induction. We thus hypothesize that EZH2 plays dual roles in prostate cancer and that combination of EPZ-6438 and AR-antagonist enzalutamide will be highly effective in fully blocking EZH2 function and eradicating CRPC. In Aim 1, we will step back to decipher the molecular mechanisms by which EZH2 induces AR gene transcription independently of its methyltransferase activity. Aim 2 will extensively delineate the catalytic and non-catalytic roles of EZH2 in regulating prostate cancer oncogenesis and most importantly evaluate the efficacy of EPZ-6438 alone or in combination with enzalutamide in suppressing CRPC using various prostate cancer models. As EZH2 depletion is much more effective than EPZ-6438 in blocking the dual roles of EZH2, in Aim 3 we propose to develop next-generation small molecule EZH2 inhibitors that are capable of degrading the EZH2 protein and test the efficacy of the lead compounds in blocking EZH2 function and suppressing CRPC progression. Ultimate Applicability of the Research: Our study will address the long-lasting problem in effectively targeting EZH2 in CRPC, providing both mechanistic insights and clinical solutions. We have discussed with Epizyme regarding the preclinical study and a potential clinical trial in the near future. Epizyme has agreed to provide us EPZ-6438 analog for the proposed preclinical studies in vitro and in animal models and showed a strong interest in continuous collaboration on a clinical trial in prostate cancer. Our preliminary data strongly support that the preclinical data will be supportive of combinatorial EPZ-6438 and enzalutamide treatment in metastatic CRPC patients. The combination is expected to significantly delay the onset of drug resistance and to prolong disease-fee survival of late-stage CRPC patients. Moreover, EPZ-6438 has been recently acquired by NCI CTEP (National Cancer Institute Cancer Therapy Evaluation Program) through an agreement with Epizyme, which make it readily available for investigator-initiated clinical trials. We predict that we will have collected the essential preclinical data regarding the drug combination by the end of year 2 and expect to achieve a patient-related outcome by initiating a Phase I clinical trial in years 2-3. A potential risk of the drug combination is toxicity, although as single agent both E
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710406
Entities
People
- Gary E Schiltz
Organizations
- Northwestern University
- United States Army