Defining the Endocrinology of Neuroendocrine Prostate Cancer to Identify Microenvironment Drivers of Treatment Resistance
Abstract
Scientific Objective and Rationale: While the vast majority of prostate cancers (PCs) are adenocarcinomas with secretory epithelial features and an active androgen receptor (AR) program, PCs with a spectrum of other histological characteristics also occur. Among these are PCs with characteristics of neuroendocrine (NE) cells. These prostate neuroendocrine carcinomas (NEPCs), representing <1% of all localized PCs, exhibit features found in NE carcinomas arising in other organs and tissues. In the context of localized NEPC, the origin of these tumors has not been conclusively established as they may arise from resident benign neuroendocrine cells or from stem-like, basal or luminal cells that usually serve as the cell of origin for typical adenocarcinoma. In the setting of metastatic PC (mPC), tumors with NE features are more common, ranging from 10-30% depending on the markers used for classification and the disease state with respect to the application of therapeutics that suppress AR signaling. Preclinical models have demonstrated the occurrence of transdifferentiation whereby tumor cells with a typical epithelial phenotype and active AR program lose AR activity and gain NE characteristics during the development of resistance to AR repression. With the advent of more potent AR signaling inhibitors (ARSI) such as abiraterone and enzalutamide, the frequency of tumors with NE phenotypes is increasing. While pure NEPC is evident in some tumor biopsies, including a subset with small cell histology that is indistinguishable from small cell carcinomas arising in other organs such as the lung, other tumors show mixtures of ARPC and NEPC cells indicating a degree of intratumor heterogeneity. Neuroendocrine small cell carcinomas are primarily characterized by morphological features, lack of AR expression, and a higher expression of several canonical markers reflecting NE cell differentiation, e.g., the transcriptional factors ASCL1, NEUROD1, INSM1, as well as function, e.g., the secreted proteins synaptophysin (SYP), chromogranin A (CgA) and neuron specific enolase (NSE). To date, the role of these and other NE secreted factors in terms of endocrine and paracrine effects toward tumor cells and local microenvironments has not been established. This research project is specifically designed to bridge this knowledge gap. The research objectives are to: (1) identify the spectrum of NEPC-derived secreted factors with the potential for adverse paracrine/endocrine activity, (2) determine the influence of NEPC cells on the growth and treatment resistance of ARPC cells, and (3) determine the role of individual secreted factors in the ARPC growth and survival program with an intent to identify druggable targets to develop novel therapies. Applicability of Research: This research is applicable to patients diagnosed with mPC and specifically those PCs with small cell and NE features – either exclusively, or intermixed with conventional ARPC. Currently, there are no therapies that can effectively treat metastatic NEPC beyond platinum-based chemotherapy. Further, the output of this project may be applicable to patients with ARPC undergoing AR-directed therapy. It is evident that AR antagonism can promote the emergence of NEPC, and co-existing NEPC cells have the potential to drive AR pathway resistance. Finally, there are a subset of patients that exhibit paraneoplastic syndromes whereby the secretory component of tumor cells produces adverse systemic effects. The successful outcome of this project could produce strategies that repress such events. The research plan involves studies in highly relevant preclinical models that reflect the biology of contemporary ARPC/NEPC. A subset of candidate therapeutic targets have clinical grade inhibitors already developed. The advancement into clinical testing could occur within 3-5 years. Principal Investigator’s Goals in Prostate Cancer Research: My career goal is to conduct
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310096
Entities
People
- Tarana Arman
Organizations
- Fred Hutchinson Cancer Center
- United States Army