# Molecular mechanisms underlying lineage plasticity in prostate cancer

> **NIH NIH R37** · DANA-FARBER CANCER INST · 2022 · $594,606

## Abstract

Project Summary/Abstract
Prostate cancer arises as an androgen driven disease, and systemic therapies that target the
androgen receptor (AR) are used to treat patients at all stages of the disease. In recent years, with
the earlier and more potent targeting of the AR with newer drugs, AR-independent prostate cancer
has emerged. We have found that this is associated with lineage plasticity in which upon selective
therapeutic pressure, tumors evade AR-therapy through loss of luminal prostate identity (including
AR) and the acquisition of alternative lineage programs including neuronal/neuroendocrine, stem-like,
and developmental pathways. In extreme cases, tumors may completely transition from an AR-
positive prostate adenocarcinoma (PADC) toward an AR-negative small cell/neuroendocrine
carcinoma (NEPC). This phenotypic change is associated with clinical and molecular features similar
to small cell lung cancer, manifest by rapid progression and lethal disease. We have integrated
patient and preclinical data to identify and molecularly characterize genes and pathways that drive
lineage plasticity including the combined loss of TP53/RB1, suppression of the Notch signaling
pathway, and up-regulation of lineage-determining transcription factors (LDTFs) including ASCL1 and
INSM1. We hypothesize that loss of Notch signaling activates LDTFs, which act coordinately with
super-enhancers and chromatin regulators to drive lineage plasticity, loss of AR signaling
dependence, and NEPC progression. To test this hypothesis, we will investigate the role of NOTCH-
INSM1 signaling in regulating LDTFs to drive NEPC progression and treatment resistance (Aim 1);
extensively characterize the super-enhancer landscape and transcriptional reprogramming that
governs lineage plasticity (Aim 2); and elucidate the transcriptional network of LDTFs that promote
tumor evolution from an AR-driven state towards non-AR driven disease (Aim 3). This proposal will
not only enhance our understanding of tumor evolution and cell identity, but will also identify new
therapeutic approaches to target lineage plasticity. These are critical steps towards improving the
early detection, treatment, and mortality of prostate cancer patients developing treatment resistance.
Results may also have relevance in other cancer types that develop lineage plasticity to evade
effective targeted therapies, such as lung cancer, melanoma, and breast cancer.

## Key facts

- **NIH application ID:** 10375455
- **Project number:** 5R37CA241486-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Himisha Beltran
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $594,606
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375455

## Citation

> US National Institutes of Health, RePORTER application 10375455, Molecular mechanisms underlying lineage plasticity in prostate cancer (5R37CA241486-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10375455. Licensed CC0.

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