Overcoming Drug Resistance of Castration-Resistant Prostate Cancer

Grants and Contracts Details

Description

Title: Overcoming drug resistance of castration-resistant prostate cancer Abstract Because androgen receptor (AR) signaling is essential for development of prostate cancer (PCa), including castration-resistant prostate cancer (CRPC), androgen signaling inhibitors (ASI) are becoming the first line treatment for CRPC. However, the limited success of ASIs makes it urgent to develop approaches to treat ASI-resistant CRPC. EZH2 (enhancer of zeste homolog 2), the catalytic subunit of the Polycomb Repressive Complex (PRC2) responsible for H3K27me3 and gene repression, has been identified as a promising target in PCa. However, it was also discovered that oncogenic function of EZH2 in CRPC is PRC2-independent. Thus, identifying regulators that control EZH2 function is of significance as it may provide an avenue to enhance the efficacy of EZH2 inhibitors (EZH2i) in CRPC. The long-term goals of this study are to identify druggable signaling pathways that offer effective treatment options for patients with ASI-resistant CRPC. The objective is to define the role of polo-like kinase 1 (Plk1) in regulating EZH2, to exploit this pathway as a therapeutic target for ASI-resistant CRPC patients, and to examine whether Plk1-dependent phosphorylation of EZH2 is a novel biomarker for CRPC. The central hypothesis is that Plk1 phosphorylation of EZH2 leads to a functional switch from PRC2-dependent gene repression to PRC2-independent but AR- dependent transcription activation, eventually contributing to disease progression into CRPC stage. Our data show that Plk1 inhibition leads to an increased level of H3K27me3 and that Plk1 directly phosphorylates EZH2 at T144. We also show that Plk1 phosphorylation of EZH2 results in decreased levels of H3K27me3, destabilization of the PRC2 complex and increased association between EZH2 and AR. Our hypothesis will be tested by pursuing three Aims - (1) to dissect how Plk1 phosphorylation of EZH2 regulates the PRC2 complex; (2) to test whether expression of unphosphorylatable EZH2 antagonizes PCa progression and enhances the efficacy of EZH2i in genetically engineered mouse (GEM) models; and (3) to determine whether Plk1 inhibitor (Plk1i) plus EZH2i is a novel approach to treat ASI-resistant CRPC and whether pT144-EZH2 is a novel biomarker for CRPC. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with inducible PCa mouse models, culture systems and patient-derived xenograft (PDX) methodologies. The rationale for the research is that it will probe the importance of Plk1 to PRC2 complex, examine whether a combination of Plk1i with EZH2i is a novel approach to treat ASI-resistant CRPC and ask whether pT144-EZH2 is a new biomarker to predict PCa progression. This contribution is significant because, if positive, the results of the proposed study will support an immediate clinical trial for Plk1i plus EZH2i to treat ASI-resistant CRPC. The research is innovative as it approaches the disease from a novel Plk1 signaling pathway, challenging the traditional view that Plk1 functions solely to regulate mitotic events.
StatusActive
Effective start/end date9/1/116/30/27

Funding

  • National Cancer Institute: $579,016.00

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