# NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2020 · $577,631

## Abstract

Androgen deprivation therapy (ADT) is effective in treating metastatic prostate adenocarcinoma (PADC), but all
patients inevitably relapse with castrate resistant prostate cancer (CRPC). Most CRPCs remain dependent on
androgen receptor (AR) signaling, but a significant fraction lack AR expression, become AR signaling
independent, and aberrantly express neuroendocrine lineage markers (NEPC). The incidence of NEPC
variants among CRPC has increased as more patients benefit from improved ADTs like enzalutamide and
abiraterone acetate. This suggests increasingly stringent AR signaling blockade is driving development of
NEPC. This is an important clinical problem because NEPC is aggressive and lethal; development of effective
therapies is hampered by limited understanding of relevant molecular mechanisms. NEPC clearly arises from
ARpos CRPC as they share clonal origin in patients that harbor both. We have determined that genetic
inactivation of the RB1/TRP53 tumor suppressor genes cooperate to facilitate transformation of ARpos PADC to
NEPC through derepression of epigenetic reprogramming factors. Inhibiting these reprogramming factors
reverses NEPC transformation and restores ADT sensitivity, demonstrating that epigenetic changes are
involved. We hypothesize that a change in NOTCH-ASCL1 signaling triggers the epigenetic
reprogramming underlying NEPC transformation. This hypothesis has clinical ramifications as the pathway
could conceivably be manipulated therapeutically to delay or reverse NEPC transformation, extending the
duration of beneficial ADT clinical responses in some patients. We propose three specific aims using novel
prostate cancer mouse models and unique human clinical specimens to test this hypothesis, characterize how
PADC cells transform into NEPC cells, and explore novel therapeutic approaches for the treatment of this
lethal form of prostate cancer. We will: 1) Test if NOTCH signaling is sufficient to maintain an androgen
dependent PADC phenotype; 2) Characterize how prostate cancer cells transition from PADC to NEPC; 3)
Determine whether epigenetic modulating drugs reverse NEPC transformation and ADT resistance via
NOTCH-ASCL1 signaling. The long term goal of this project is to improve prostate cancer therapy by
advancing mechanistic understanding of lineage plasticity as a mechanism of acquired therapeutic resistance.

## Key facts

- **NIH application ID:** 9933837
- **Project number:** 5R01CA234162-02
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** DAVID W. GOODRICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $577,631
- **Award type:** 5
- **Project period:** 2019-05-22 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933837

## Citation

> US National Institutes of Health, RePORTER application 9933837, NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer (5R01CA234162-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9933837. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*