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

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2022 · $351,338

## Abstract

ABSTRACT:
Estrogen receptor-positive (ER+) disease represents greater than 70% of new breast cancer cases and is
treated with endocrine-therapy and CDK4/6 inhibitors in the metastatic setting. While these approaches have
clinical impact, veritably all patients ultimately progress on treatment. Conventionally, CDK4/6 inhibitors
function by inhibiting cellular proliferation by inhibiting progression through G1/S phase of the cell cycle.
However, an ever-increasing collection of data indicate that the systemic delivery of CDK4/6 inhibitors has
broad effects on both the tumor (e.g. adaptive signaling and metabolism) and the associated microenvironment
(e.g. immunological milieu). This complexity in mechanism of action is likely relevant for the response to
therapy and acquisition of resistance and disease progression. The corollary of which, is that by fully
understanding the functional drivers of resistance new interventions could be developed to enhance the
durability of response or treat progressed disease.
 One of the challenges in studying ER+ breast cancer is the lack of robust mouse models. As shown
in the preliminary data, using intraductal injection a robust mouse model for ER+ luminal breast cancer has
been developed. We will use this model to interrogate the impact of CDK4/6 inhibition on the multi-focal
tumors that arise in this model with an emphasis on both the canonical effects on cell cycle as well as re-
programming within the tumor microenvironment. For this work we will use multi-spectral imaging and single
cell sequencing approaches as we have recently published for tumor characterization and immunological
features of the disease. These models are amenable to somatic genetic manipulation that also enable drivers
of therapeutic resistance in vivo (Aim 1). Since many patients are being treated with CDK4/6 inhibitors, there
are progressively more patients whose tumors have progressed on therapy. In recognition that
understanding the real world experience is important, we initiated a clinical study to longitudinally follow
patients who are being treated or whose tumors have progressed on CDK4/6 inhibitor based therapy. In
metastatic breast cancer it is common to biopsy progressive disease to evaluate routine clinical biomarkers;
therefore, for many patients we are collecting multiple tissue specimens. Here we will use this collection of
tissues to define biological features of the tumors with a focus on proteins and spatial features of the tumor that
are lost with typical molecular analyses (Aim 2). The data from these two Aims will be integrated to rigorously
delineate the mechanisms of resistance to CDK4/6 inhibition in ER+ breast cancer.

## Key facts

- **NIH application ID:** 10436675
- **Project number:** 3R01CA247362-03S1A1
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Erik Knudsen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $351,338
- **Award type:** 3
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436675

## Citation

> US National Institutes of Health, RePORTER application 10436675, RB tumor suppressor as a therapeutic target in ER-positive breast cancer (3R01CA247362-03S1A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10436675. Licensed CC0.

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