EZH2 as a therapeutic target for aggressive prostate cancer

Latarani, Maryam; Pucci, Perla; Roig Carles, David; Eccleston, Mark; Xue, Hui; Hawkes, Cheryl; Rigas, Sushila; Wang, Yuzhuo and Crea, Francesco (2020). EZH2 as a therapeutic target for aggressive prostate cancer. In: Crick Cancer Research Symposium, iPoster, 5-6 Oct 2020, The Francis Crick Institute and Virtual.

Abstract

Aggressive variants of prostate cancer (AVPC) are a subtype of metastatic castration resistant prostate cancer (mCRPC), which express no androgen receptor (AR) and are currently incurable. The main AVPC subtypes are neuroendocrine prostate cancer (NEPC) and anaplastic prostate cancer (AR-, NEPC-). EZH2 is an epigenetic regulator that mediates gene silencing via histone H3 Lys27 trimethylation (H3K27me3). EZH2 acts as an oncogene in several malignancies. Three pharmacologic EZH2 inhibitors (Tazemetostat, GSK-126, and CPI-1205) are in clinical trials. Volition Nu.Q kits enable the detection of histone variants in biological fluids. We hypothesize that EZH2 could be a viable therapeutic target for AVPC.
We queried the expression of EZH2 in a database comprising 444 mCRPC clinical samples. Our results show that higher EZH2 expression is positively correlated with NEPC features (p<<0.0001, T test), and negatively correlated with AR activity (p< 4.57e-11). Higher EZH2 expression predicts shorter overall survival (p< 0.0276, log-rank test).
The three EZH2 inhibitors induce a dose-dependent inhibition of cell proliferation in two AVPC cell lines (DU-145, PC-3). GSK-126 is the most potent inhibitor. Total histone H3 and H3K27me3 are measurable in the supernatant from AVPC cell lines (Nu.Q assay). Treatment with EZH2 inhibitors induces a measurable reduction in H3K27me3. We are now testing the interaction between GSK-126 and chemotherapy drugs employed for the treatment of AVPC. We are also testing Nu.Q kits in blood samples from patient-derived xenografts. This information will be useful to develop tailored epigenetic therapies for AVPC patients.

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