# Defining Molecular Determinants of Lineage Plasticity as a Mechanism of Treatment Resistance in Prostate Cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $428,090

## Abstract

Project Summary/Abstract
Prostate cancer arises as an androgen driven disease and therefore therapies targeting the androgen receptor
(AR) have been a major focus of prostate cancer treatment. Despite recent advances in the development of
highly effective AR-directed therapies, the development of acquired resistance remains a significant challenge.
An emerging concept of anti-AR resistance is the induction of epithelial plasticity to a heterogeneous state that
has lost its AR-dependent luminal identity and ultimately develops neuroendocrine prostate cancer (NEPC).
There are no effective therapies for patients with NEPC and prognosis is extremely poor (average survival = 7
months). NEPC retains many of the genomic alterations that arise in prostate adenocarcinoma castration
resistant prostate adenocarcinoma suggesting a clonal origin. Recently, we and others have identified and
validated new therapeutic targets and drivers of cell transformation from CRPC to NEPC (e.g. induction of
MYCN (encodes N-Myc) or loss of Retinoblastoma-1 (RB1) and TP53. We have shown that N-Myc is over-
expressed in the majority (>95%) of NEPC cases and in 20% of CRPC tumors that also display features of
NEPC. RB1 loss occurs in majority of NEPC cases (70%) and in 32% of CRPC tumors which overlaps, in part,
with N-Myc over-expression. Currently, the synergy between MYCN induction and RB1 loss, mechanisms
downstream of induction of MYCN induction/PTEN loss with or without RB1 loss in driving lineage switching
and treatment response are not well understood. Our over-arching hypothesis is that specific molecular
alterations (e.g. MYCN induction) in prostate cancer cells drive lineage plasticity by establishing a molecular
program associated with the neural lineage and epigenomic reprogramming as a mechanism of resistance to
anti-AR therapy and transformation towards a neuroendocrine phenotype. To address this hypothesis we have
formulated the following three Specific Aims: We will use murine and human in vitro, in vivo and ex vivo models
to establish the role of N-Myc and downstream mediators (e.g. NKX2-1, SOX11,) in gene expression and
epigenetic reprogramming driving CRPC-Adeno towards NEPC (Aim 1); we will also define essential N-Myc-
transcriptional complex proteins that mediate the transition from CRPC-Adeno towards NEPC (Aim 2); finally,
we will evaluate the preclinical efficacy of therapy targeting CRPC-Adeno to NEPC transition (Aim 3). We
expect that during the transformation process and before epigenetic hardwiring, tumor cells will retain the
capacity to revert to a luminal phenotype as a result of molecular or pharmacological intervention. This project
leverages unique model systems to study drivers of lineage switching and treatment response. The
multidisciplinary project builds upon a long-standing collaboration between the PI and co-Is and extensive
preliminary data. At the conclusion of this study, we will have a better understanding of the mechanisms
underlyi...

## Key facts

- **NIH application ID:** 9985075
- **Project number:** 5R01CA230913-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** David S. Rickman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $428,090
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985075

## Citation

> US National Institutes of Health, RePORTER application 9985075, Defining Molecular Determinants of Lineage Plasticity as a Mechanism of Treatment Resistance in Prostate Cancer (5R01CA230913-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9985075. Licensed CC0.

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