# NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2021 · $48,583

## Abstract

Summary
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 these NEPC
variants 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. NEPC is aggressive
and lethal, thus reflecting a growing clinical problem. 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 Notch signaling
within the tumor microenvironment suppresses the epigenetic reprogramming underlying NEPC
transdifferentiation. 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. This administrative diversity supplement application is proposed to support
Mauricio Flores, a predoctoral student who will be involved in the parent R01 grant supported research program
characterizing the role of NOTCH signaling in NEPC transdifferentiation. The research, mentoring, and career
development plan proposes three research aims: 1) Identify organoid culture conditions sufficient to support
NEPC transdifferentiation in vitro; 2) Test how Notch signaling affects NEPC transdifferentiation in vitro; 3)
Identify stromal-cancer cell interactions that influence NEPC transdifferentiation in vitro. The long-term goal of
this diversity supplement is to facilitate Mr. Flores' cancer research career development and to improve prostate
cancer therapy by advancing mechanistic understanding of lineage plasticity as a mechanism of acquired
therapeutic resistance.

## Key facts

- **NIH application ID:** 10346091
- **Project number:** 3R01CA234162-03S1
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** DAVID W. GOODRICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $48,583
- **Award type:** 3
- **Project period:** 2019-05-22 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10346091

## Citation

> US National Institutes of Health, RePORTER application 10346091, NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer (3R01CA234162-03S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10346091. Licensed CC0.

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