Targeting EZH2 in Castration-Resistant Prostate Cancer
Technical Report,01 Aug 2017,31 Jul 2018
Northwestern University Evanston United States
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Metastatic castration-resistant prostate cancer CRPC is a major cause of prostate cancer-associated mortality. Genesproteinsthat drive or sustain CRPC tumor growth and metastasis are promising targets for therapeutic intervention. EZH2 enhancer ofzest 2, an enzyme that catalyzes histone 3 lysine 27 trimethylation H3K27me3, was found among the most up-regulatedgenes in CRPC and strongly promotes disease progression. Surprisingly, enzymatic EZH2 inhibitors such as EPZ-6438 alsocalled Tazemetostat, Epizyme has limited efficacy in prostate cancer, suggesting that EZH2 may play non-catalytic roles inprostate cancer. Our preliminary data suggest androgen receptor AR as a critical target and mediator of the non-catalyticroles of EZH2. We found that EZH2 can directly induce the transcription of the AR gene and that enzymatic EZH2 inhibitorsfailed to block AR induction. We hypothesize that EZH2 plays dual roles in prostate cancer and that combination of EPZ-6438with AR pathway inhibitors will be highly effective in fully blocking EZH2 function and thus suppressing CRPC.
- Medicine and Medical Research