Determining the Contribution of Lineage Intermediate Tumor Cells During Progression to t-SCNC
Abstract
Targeting of the androgen receptor (AR) provides significant benefits for individuals with localized and metastatic prostate cancer. However, an increasing clinical observation is the prevalence of prostate cancers that have adapted to the continued suppression of AR expression and function. Clinical examples of such adapted therapies include treatment related small cell neuroendocrine prostate cancer (t-SCNC) and prostate cancers with mesenchymal signatures. Since t-SCNC is poorly responsive to most standard-of-care therapies and has poor clinical outcomes, there is a need to model and understand how ADT (androgen deprivation therapy) induces the evolution of prostate adenocarcinomas to lethal disease subtypes that are no longer responsive to AR targeting agents. An emerging mechanism for the occurrence of neuroendocrine and mesenchymal tumors is through lineage switching or plasticity—a process whereby one cell type can take on features of another lineage or cell type. During this progression, we propose that tumor cells must transition through intermediate cellular phenotypes including the coordinate expression of luminal-epithelial and neuroendocrine or mesenchymal lineage markers. Intermediate subpopulations may be identified by unique transcriptional, epigenetic, and pathological signature(s). Thus, we propose that intermediate subpopulations may present a rate-limiting step that is required for cells destined to become neuroendocrine or mesenchymal. We have developed new patient-derived tumor models and lineage reporters in efforts to target and reprogram luminal-neuroendocrine, intermediate cell populations through hormone replacement therapy, genetic approaches, and novel small molecule inhibitor targeting repressive epigenetic events. Our studies will address the complex clinical challenge of treatment resistance and lethal disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310186
Entities
People
- David Mulholland
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army