Exploiting RNA Epitranscriptomes for the Treatment of Lethal Neuroendocrine Prostate Cancer
Abstract
Rationale and Objective: Prostate cancer-related deaths are attributable to metastatic disease, for which androgen deprivation therapy (ADT) with antiandrogen has been the main intervention. Although this therapy is initially effective, essentially all patients progress and develop castration-resistant prostate cancer (CRPC), which is at present incurable. Thus, an important therapeutic objective is to discover new targets and mechanisms of resistance in CRPC that overcome resistance to ADT. CRPC relapsing from ADT arises in the absence of a functional androgen receptor as a highly metastatic and lethal prostate cancer variant, termed neuroendocrine prostate cancer (NEPC). Although rarely occurring de novo, the treatment-related NEPC derived from prostatic adenocarcinoma (PADC) can arise in about 25% or more late stage CRPC, which is notoriously hard to treat and resistant to ADT. Thus, there is an urgent clinical need for novel targets and therapies. However, molecular mechanisms underlying the transformation of PADC to NEPC are not clear, nor are there targeted therapies available to treat lethal NEPC. NEPC has few genomic alterations, suggesting that NEPC transdifferentiation and ADT resistance are driven by epigenetic factors. N6-methyladenosine (m6A) is the most common and abundant RNA modification (epitranscriptome). Despite its functional importance in various normal bioprocesses, including tissue development and cell identity, the biological role and clinical significance of m6A RNA modification, as well as its target genes and regulatory signaling pathways in prostate cancer, are currently unknown. Our overarching goal centers on the most important issue facing patients with CRPC, that of predicting and overcoming treatment resistance. As the next step toward that goal, we propose to identify the epigenetic mechanisms underlying lethal metastatic NEPC, thereby enabling accurate patient stratification for the rational design of promising new therapies. Our preliminary data show that m6A RNA modification is aberrantly regulated in human and mouse lethal metastatic NEPC, predominantly owing to PTEN loss, controls NEPC transdifferentiation, and confers resistance to ADT. In this grant, a series of genetic and clinical settings will lead to discovery of a novel PTEN-integrated m6A RNA methylation signaling network in the development of lethal NEPC; this finding will be highly novel because the mechanism by which PTEN dictates dynamic RNA epitranscriptome is yet unexplored. Further, we will determine how m6A triggers the PADC to NEPC transition associated with resistance to ADT. The success of the first two studies will lead us to evaluate the preclinical efficacy of combined targeting of m6A and androgen receptor for lethal NEPC. Ultimate Applicability for Treating Prostate Cancer: The successful completion of this project will develop pharmacological blockade of m6A RNA modification, as a single agent and in combination with ADTs such as casodex and enzalutamide, to generate promising therapeutics against lethal metastatic castration-resistant NEPC, paving the way for preclinical efficacy studies. If all goes smoothly, a Phase I/II clinical trial could be initiated within 1-2 years of completing this study. Interim Outcomes: This proposal builds on basic discoveries and observations from our group and suggests alternate pathways and mechanisms for treatment resistance, metastasis, and mortality of prostate cancer and will develop novel targeted therapies to delay and/or reverse the NEPC lineage switch, extending the durability of clinically beneficial ADT responses. The eventual translation of our cutting-edge research to the clinic will be an important step forward for worldwide public health. Likely Contributions to Advancing Prostate Cancer Research: NEPC is a lethal subset of metastatic CRPC with aggressive clinical features and poor overall survival. However, molecular mechanisms unde
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010379
Entities
People
- Min Sup Song
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army