# Exploiting RB1 deficiency for the treatment of lethal neuroendocrine prostate cancer

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2020 · $505,760

## Abstract

Metastatic prostate cancer is incurable with available therapies and accounts for all prostate cancer mortality.
This is a significant health problem given that prostate cancer is the most common visceral cancer in men and
the second leading cause of cancer death in western societies. Androgen deprivation therapy (ADT) is the
most generally useful therapy available. Despite the initial effectiveness of this molecularly targeted therapy,
however, patients will inevitably relapse with ADT resistant disease. Well characterized forms of ADT
resistance include alterations in androgen receptor (AR) leading to persistent and sometimes ligand
independent AR signaling as well as changes in steroid metabolism that maintain intratumoral androgen levels
sufficient for AR signaling. Newer generation drugs like the superior AR antagonist enzalutamide or the
CYP17A1 inhibitor abiraterone acetate counter these ADT resistance mechanisms and extend life in men with
recurrent disease, but responses have proven short lived. Delaying or reversing ADT resistance, therefore, is
an important therapeutic goal as it is proven to extend patient survival. As AR blockade has improved, a unique
form of resistance involving trans differentiation to an AR negative cancer with neuroendocrine features
(NEPC) is increasingly observed. NEPC progresses with atypical visceral metastasis in the absence of rising
PSA, and is observed currently in about 25% of prostate cancer autopsies. Incidence is likely to increase as
more patients benefit from improved ADT. Molecular mechanisms underlying NEPC trans differentiation are
not clear, nor are there targeted therapies available to treat it. We present data from human cell lines and
mouse models suggesting RB1 loss is a key determinant facilitating NEPC trans differentiation. We suggest
Rb1 loss relieves a constraint on epigenetic reprogramming of gene expression thereby facilitating
trans differentiation to AR negative, ADT resistant NEPC. If true, NEPC trans differentiation should be
reversible. Consistent with this prediction, preliminary data indicates some epigenetic modulating drugs restore
AR expression and enzalutamide sensitivity in NEPC. The specific goals of the proposed research are to
challenge the central hypothesis, characterize mechanisms causing NEPC trans differentiation, assess their
clinical relevance by cross-species analysis, and test their utility as therapeutic targets using pre-clinical trials.
Successful completion of these goals will address a critical issue in the clinical management of prostate cancer
and will fill major current gaps in our fundamental understanding of prostate cancer progression, therapeutic
resistance, and the role that RB1 loss of function plays in these processes.

## Key facts

- **NIH application ID:** 9994250
- **Project number:** 5R01CA207757-05
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Leigh Ellis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $505,760
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994250

## Citation

> US National Institutes of Health, RePORTER application 9994250, Exploiting RB1 deficiency for the treatment of lethal neuroendocrine prostate cancer (5R01CA207757-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9994250. Licensed CC0.

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