# Project 3: Therapeutic Targeting of Lineage Plasticity in Castration-Resistant Prostate Cancer > **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $177,336 ## Abstract ABSTRACT/SUMMARY The clinical success of androgen receptor signaling inhibitors such as abiraterone and enzalutamide has significantly extended survival for men with castration-resistant prostate cancer (CRPC), but metastatic CRPC tumors inevitably acquire resistance to these agents through a variety of mechanisms. Of particular concern, due to the increased aggressiveness and lethality, is the development of lineage plasticity: when the tumor transitions from a classical, androgen receptor (AR)-positive, prostate-specific antigen (PSA)-expressing adenocarcinoma to an AR-low/negative, PSA-low tumor with undifferentiated or neuroendocrine/small cell histology. These tumors display considerable heterogeneity in expression of various marker genes, including AR, luminal cytokeratins such as CK8, and neuroendocrine markers such as synaptophysin or chromogranin. This heterogeneity is an anticipated consequence of the underlying lineage plasticity of these tumor cells but leads to confusion in how to precisely define this transition stage, particularly for the purpose of eligibility for clinical trials. Recent insights from tumor sequencing have identified additional features associated with lineage plasticity, such as genomic alterations in TP53 and RB1, increased expression of EZH2 and SOX2, and activation of stem-like RNA signatures, but none of these currently serve as a validated biomarker. In addition to the diagnostic challenges, this magnitude of heterogeneity raises obvious concerns about the feasibility of successful therapeutic intervention. Our perspective is that this challenge can be addressed only if we have a more detailed understanding of the magnitude of heterogeneity and the underlying molecular drivers of that heterogeneity. Toward that end, we have deployed RNA sequencing and spatial imaging technologies to characterize intra- and inter-tumoral heterogeneity in CRPC at a single-cell level. Based on our initial leads, we will be investigating inhibitors of JAK kinases, FGFR, EZH2, and p300/CBP in preclinical models using patient- derived organoids and xenografts, to understand these agents’ activity against CRPC that has developed lineage plasticity. Another major goal of this project is to address this diagnostic challenge by evaluating these markers in blood-based assays such as circulating tumor cells (CTCs) and cell-free tumor DNA (cfDNA) (Aim 3). To that end, we will evaluate the frequency of DLL3 expression and additional CTC/cfDNA biomarkers representing therapeutic targets in Aim 2, and investigate morphologic, phenotypic and genomic heterogeneity within biomarker-positive CTC sub-populations. Finally, we will investigate whether persistent CTC subpopulations can be utilized to provide an early indication of response, identify potential resistance mechanisms, and guide future therapeutic development. The primary goal of this project will be to leverage our findings, including focusing on the use of single-cell technology to f... ## Key facts - **NIH application ID:** 10915674 - **Project number:** 5P50CA092629-23 - **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH - **Principal Investigator:** CHARLES L. SAWYERS - **Activity code:** P50 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $177,336 - **Award type:** 5 - **Project period:** 2001-09-14 → 2027-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10915674 ## Citation > US National Institutes of Health, RePORTER application 10915674, Project 3: Therapeutic Targeting of Lineage Plasticity in Castration-Resistant Prostate Cancer (5P50CA092629-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10915674. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*