PRMT5/MEP50 as a Critical Epigenetic Regulator and Therapeutic Target for Therapy-Induced Neuroendocrine Prostate Cancer
Abstract
Prostate cancer remains the second leading cause of cancer death among American men according to American Cancer Society. The vast majority of prostate cancer death is due to the development of castration-resistant prostate cancer (CRPC), a lethal and end stage of the disease, after androgen deprivation therapy (ADT), also known as hormone therapy. Despite multiple mechanisms that may underlie the development of CRPC, neuroendocrine differentiation (NED), a process by which prostate cancer cells change into neuroendocrine prostate cancer (NEPC), represents an emerging and important mechanism. In fact, therapy- induced NEPC (t-NEPC) constitutes more than 25% of all CRPC. NEPC cells are male hormone receptor androgen receptor (AR) negative and do not secret prostate-specific antigen (PSA). NEPC is highly aggressive, with an average survival rate of less than 1 year. Presently, there is no effective treatment for NEPC. Importantly, all existing treatments including the two second-generation androgen-signaling inhibitors abiraterone and enzalutamide, chemotherapeutic agent docetaxel, and radiation therapy can cause NEPC development. Thus, inhibiting the development of t-NEPC during these anti-androgen signaling treatments will increase the efficacy of the existing anti-androgen treatments. More importantly, developing an effective treatment for NEPC will provide an urgently needed option to manage this deadly disease. We have recently identified protein arginine methyltransferase 5 (PRMT5), an emerging family of enzymes that alter expression of genes without causing any change in DNA sequence, as a critical regulator of prostate cancer cell growth. Further, PRMT5 is overexpressed in prostate cancer tissues, in particular, in CRPC. Interestingly, PRMT5 expression is highly induced by ADT, and it is significantly overexpressed in NEPC. Along with PRMT5 overexpression, the methylsosome protein 50 (MEP50) is also co-expressed in NEPC. MEP50 is a protein that interacts with PRMT5 and forms an enzymatic active complex with PRMT5. Thus, MEP50 is considered an obligate cofactor for PRMT5. Preliminary studies have revealed that PRMT5 and MEP50 mediate ADT- and ASI-induced NED and that they are required for the maintenance and survival of NEPC cells. Based on these novel findings, we hypothesize that the PRMT5/MEP50 complex is a critical regulator and therapeutic target of therapy-induced NED and NEPC. To test this novel hypothesis, we will pursue two specific aims. In Aim 1, we will use our transgenic mouse models that co-express PRMT5 and MEP50 in mouse prostate cancer to evaluate whether their co-expression promotes NED and NEPC in the background of a well-established Pten Knockout mouse prostate cancer. Additionally, we will determine whether PRMT5/MEP50 co-expression can potentiate the induction of NED and the development of NEPC. Finally, we will use human prostate cancer tissues and NEPC tissues to establish the clinical significance of the PRMT5/MEP50 co- expression in t-NEPC. In Aim 2, we will evaluate the therapeutic potential of targeting PRMT5 with a potent inhibitor JNJ-64619178 as a novel therapeutic approach for prevention and treatment of t-NEPC. JNJ-64619178 is a novel PRMT5 inhibitor, and it is currently in Phase I clinical trial for several other human cancers. Contribution to the FY21 PCRP Overarching Challenges: The proposed research will validate the PRMT5/MEP50 complex as a therapeutic target and evaluate the therapeutic potential of JNJ-646191798 for prevention and treatments of therapy-induced NEPC. Thus, this study will address two overarching challenges: Develop treatments that improve outcomes for men with lethal cancer and Define the biology of lethal prostate cancer to reduce death. The Types of Patients Who May Benefit from the Proposed Research: As all existing treatments can induce NED to promote development of t-NEPC and recently increased use of Abiraterone and Enza
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210332
Entities
People
- Chang Deng Hu
Organizations
- Purdue University
- United States Army