# RB tumor suppressor as a therapeutic target in ER-positive breast cancer

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2024 · $316,204

## Abstract

ABSTRACT: Our work over the last several years, indicates that cell cycle regulatory pathways are critical
determinants of the response to endocrine therapy as well as targeted therapies that are frequently employed
in the treatment of ER+ metastatic breast cancer. Here we will focus on the RB-tumor suppressor pathway as
a central node controlling proliferation downstream of multiple pathways of relevance to therapy of ER+ breast
cancer (e.g. endocrine therapy and CDK4/6 inhibitors). While RB is required for the effective cytostatic
response to a range of targeted therapies employed in ER+ breast cancer, multiple pathways can contribute to
“cell cycle plasticity” and therefore represent distinct means for generating therapeutic resistance. Here we will
delineate the processes underlying this form of resistance, means to elicit durable cell cycle arrest, and
approaches to target resistance as observed clinically (Aim 1). Our data and newly published studies indicate
that RB loss occurs in ER+ breast cancer as a means to escape from cytostatic therapies. Analysis of the RB
locus in ER+ breast cancer indicates loss of one copy of 13q occurs in a significant fraction of ER+ breast
cancers, suggesting that such tumors are primed for RB loss. How to subsequently treat tumors that are
heterogeneous for RB or are solely RB deficient represents a significant challenge. Using drug screening and
organoid approaches we have defined several regimens that are particularly effective against RB-negative
tumors and could represent a general means to target ER+ tumors that progress on CDK4/6 inhibitors (Aim 2).
Together these aims will interrogate means to further leverage the RB tumor suppressor for a precision
approach to the treatment of ER+ breast cancer.

## Key facts

- **NIH application ID:** 11010047
- **Project number:** 3R01CA247362-05S1
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Erik Knudsen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $316,204
- **Award type:** 3
- **Project period:** 2020-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11010047

## Citation

> US National Institutes of Health, RePORTER application 11010047, RB tumor suppressor as a therapeutic target in ER-positive breast cancer (3R01CA247362-05S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11010047. Licensed CC0.

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