Temporal Evolution of N-Myc Signaling and Early Targeting of the Neuroendocrine Phenotype in Prostate Cancer
Abstract
While hormonal therapies targeting the androgen receptor (AR) have significantly improved outcomes for men with advanced prostate cancer, treatment resistance commonly develops. It has been increasingly recognized that a subset of these resistant cases lose dependence or “escape” AR signaling and develop “neuroendocrine” pathology features, which is associated with the cancer’s ability to adapt in a way to evade to these types of therapies. Neuroendocrine prostate cancer (NEPC) is clinically aggressive, and median survival is less than 1 year. Late diagnosis and an incomplete understanding of the components that drive its onset can account for the poor prognosis of NEPC in part. Over the last 7 years, our groups have co-led extensive molecular analyses of NEPC from studying patients and their biopsies and have developed new NEPC mouse models to better understand the biology driving treatment resistance in advanced prostate cancer and the development of NEPC. We have identified key proteins (for example, N-Myc, Aurora kinase A, and EZH2) that work together to promote the evolution from the more common type prostate cancer (adenocarcinoma) to this lethal subgroup of NEPC. This led us to hypothesize that N-Myc is an early driver of the NEPC phenotype and that by tracking N-Myc signaling during the transition from adenocarcinoma to NEPC, we can identify other druggable proteins that work with N-Myc to promote NEPC progression and define appropriate time points for early intervention. To address this hypothesis, we aim to analyze an extensive set of prostate cancer samples from patients diagnosed and treated at various time points and clinical disease states in order to assess how the timing of N-Myc activation and NEPC signaling impacts prognosis and response to treatment (Aim 1). We will characterize a novel inducible mouse model to assess the biologic impact of timing of N-Myc expression on the development of the NEPC phenotype (Aim 2) and use this model to understand how N-Myc timing affects response to NEPC directed therapeutics (Aim 3). Our goal is to develop strategies to identify patients early (before they develop an aggressive NEPC) and implement early treatment strategies to prevent the development of resistance. The foundation of this proposal is based on several years of research led by the Principal Investigators (PIs), the largest to-date evaluation of molecular alterations associated with advanced prostate cancer including NEPC, unique clinical cohorts and preclinical model systems, and a long-standing history of productive collaboration between the PIs. Ultimate Applicability: Results from this study will lead to the identification of a new class of disease specific biomarkers and treatment strategies for patients with advanced prostate cancer by leading to better patient selection for sequencing of current therapies, early diagnosis of NEPC, and prevention of treatment resistance. This study will lead to new treatment strategies that will be directly translated to patients, making a major impact on the goal of elimination of death from prostate cancer and enhancing the well-being of men experiencing the impact of the disease. Results from this project will directly lead to clinical biomarkers and early phase biomarker driven clinical trials that will begin at the end of this 3-year project. Since transformation from common prostate cancer to the lethal NEPC subgroup of prostate cancer is accelerated by the use of hormonal therapy, there is concern that with the recent widespread clinical use of potent hormone therapies for the treatment of metastatic prostate cancer, the incidence of AR-independent NEPC will escalate as a mechanism of resistance. Therefore, findings from this study will significantly impact more patients with advanced prostate cancer than previously appreciated and will have a major impact in eliminating death from prostate cancer and enhancing the well-being of men experiencin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710652
Entities
People
- David Rickman
Organizations
- United States Army
- Weill Cornell Medicine