# Targeting m6A RNA epigenetics in treatment-emergent neuroendocrine prostate cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $370,575

## Abstract

Project Summary/Abstract
Castration-resistant prostate cancer is associated with substantial clinical, pathologic, and molecular
heterogeneity; most tumors remain driven by androgen receptor (AR) signaling, which has clinical implications
for patient selection for AR-directed therapies. However, histologic and clinical resistance phenotypes can also
emerge after prolonged AR pathway inhibition, in which the tumors become less dependent on AR signaling
(referred to as ‘androgen indifferent’). These highly aggressive and lethal tumors, termed treatment-emergent
neuroendocrine prostate cancer (t-NEPC), are clonally derived from adenocarcinoma through lineage plasticity
or transdifferentiation. There is an urgent need for novel targets and therapies for t-NEPC. t-NEPC cells carry
recurrent genetic and epigenetic alterations as an adaptive response, thus suggesting that key molecular
pathways and drivers controlling cell fate may be used as targets for therapeutic intervention. N6-
methyladenosine (m6A) is an abundant internal RNA modification in eukaryote messenger RNAs. Despite its
functional importance in different types of cancer, their specific role in prostate cancer progression and therapy
resistance still remains elusive. Our integrative analysis of phosphoproteome, epitranscriptome, transcriptome,
and ribosome profiling using in vitro and in vivo models identified m6A as exciting new epigenetic mark
underlying prostate cancer lineage transition and therapeutic resistance. We therefore hypothesize that m6A
drives lineage plasticity and is dynamically regulated by antiandrogen in prostate cancer, and that targeting
m6A can reverse the lineage transformation, thereby restoring sensitivity to antiandrogen therapy in t-NEPC.
We will test our central hypothesis by pursuing the following specific aims: (1) Determine the functional
significance of m6A RNA epigenetics for therapeutic resistance in prostate cancer; (2) Elucidate the molecular
mechanisms of m6A function in prostate cancer lineage plasticity and antiandrogen resistance; and (3)
Establish the therapeutic potential of inhibitors tageting m6A for treatment of t-NEPC. The outcomes of this
project are expected to open new avenues for t-NEPC therapeutics in linking m6A RNA epigenetics to lineage
plasticity-mediated therapy resistance, and should have a profound impact on our approach to tackle the
greatest challenges facing patients with treatment-emergent maligancies.

## Key facts

- **NIH application ID:** 10177604
- **Project number:** 1R01CA258100-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Min Sup Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $370,575
- **Award type:** 1
- **Project period:** 2021-06-04 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177604

## Citation

> US National Institutes of Health, RePORTER application 10177604, Targeting m6A RNA epigenetics in treatment-emergent neuroendocrine prostate cancer (1R01CA258100-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10177604. Licensed CC0.

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