# "DNMT and TET1 reprogramming as a targetable mechanism of resistance in advanced prostate cancer"

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $613,243

## Abstract

Project Summary/Abstract
Prostate cancer arises as an androgen driven disease and therefore androgen receptor (AR) targeting therapies
have been a major focus of prostate cancer treatment. Lineage
lose
mechanism
cancer histologic transformation from an AR-positive prostate adenocarcinoma to
an AR-negative small cell carcinoma that expresses neuroendocrine markers, often referred to as
neuroendocrine prostate cancer (NEPC). NEPC is clinically aggressive and prognosis is poor. Therefore,
effective treatment for NEPC patients remains an unmet clinical need. A thorough molecular understanding of
NEPC progression is needed for the development of effective treatments for this lethal disease. Although NEPC
tumors arise clonally from prostate adenocarcinoma and share genomic alterations, there is significant
epigenetic deregulation during the transformation process. However, mechanistically, we still do not know how
these epigenetic alterations arise and how best to leverage these alterations as a therapeutic opportunity. Our
preliminary and published data from in vivo, in vitro and ex vivo models (NEPC-patient-derived organoids)
suggest that the N-Myc transcriptome and cistrome is androgen-dependent and drives epithelial plasticity and
the acquisition of clinically-relevant, NEPC molecular program and a reprogramming of the epigenome. Most
recently, based on data from a new genetically engineered mouse model (GEMs), we found that N-Myc induction
synergizes with RB1 loss to deregulate DNA methylation readers, writers (e.g. DNMT1 and DNMT3B) and
erasures (e.g. TET1). Interestingly, we and others have shown that specific molecular or pharmacological
interventions can revert NEPC phenotype to a luminal—more clinically manageable—adenocarcinoma
phenotype. Our over-arching hypothesis, which is based on our published and preliminary data, is that specific
molecular alterations (e.g. MYCN induction/RB1 loss) in prostate cancer cells drive lineage plasticity through
epigenetic reprogramming (i.e., DNA methylation) as a mechanism of resistance to anti-AR therapy and this
leads to transformation to NEPC. To address this hypothesis, we will employ patient-derived organoids and
xenograft and novel genetically engineered mouse models to elucidate the role and specificity of DNMTs/TET1
in establishing the NEPC-related DNA methylation program (Aim 1), characterize the upstream regulation of
DNMTs expression in the progression to NEPC (Aim 2) and to assess the therapeutic potential of DNMTs
inhibition alone or in combination with AR targeted therapy to block the transition to or maintenance of NEPC
(Aim 3). Successful completion of these Aims will provide unique insights into NEPC development, identify key
and potential targetable mediators of lineage plasticity, and provide rationale for future clinical strategies to target
the underlying epigenetic mechanisms that drive the transition from prostate adenocarcinoma to NEPC.
plasticity, a process by which differentiated ...

## Key facts

- **NIH application ID:** 10844613
- **Project number:** 5R01CA274963-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Himisha Beltran
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $613,243
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844613

## Citation

> US National Institutes of Health, RePORTER application 10844613, "DNMT and TET1 reprogramming as a targetable mechanism of resistance in advanced prostate cancer" (5R01CA274963-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10844613. Licensed CC0.

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