# Determining and targeting mechanisms controlling cancer cell division

> **NIH NIH P01** · STANFORD UNIVERSITY · 2024 · $87,061

## Abstract

OVERALL SUMMARY
The Cyclin D-Cdk4/6-Rb-E2F pathway integrates external and internal signals to control cell cycle progression
at the G1/S transition of the cell cycle. Alterations in the Cyclin D-Cdk4/6-Rb-E2F pathway are found in the vast
majority of human cancers. These alterations are thought to increase the proliferative potential of cancer cells.
For example, the functional inactivation of the retinoblastoma (RB1) tumor suppressor or the amplification of
Cyclin D genes is a recurrent event in the development of a wide range of human cancers. In the simple
consensus model, the retinoblastoma protein Rb inhibits cell proliferation at the G1/S transition of the cell cycle
by binding and inhibiting E2F transcription factors. In response to cell growth and proliferative signals, Rb is
phosphorylated and inactivated in normal cells by a series of Cyclin-dependent kinase complexes (first Cyclin
D-Cdk4/6 and then Cyclin E/A-Cdk2). Phosphorylation of Rb results in the dissociation of Rb from E2F
transcription factors thereby causing transcription of genes important for DNA synthesis and other key aspects
of cell cycle progression. Thus, cancer cells with constitutively inactive Rb are thought to acquire an increased
proliferative potential. Knowledge of the Cyclin D-Cdk4/6-Rb-E2F pathway in normal and cancer cells has led to
the development of specific Cdk4/6 inhibitors that have been approved for the treatment of breast cancer and
are in clinical trials for several other cancer types. In this paradigm, inhibition of Cdk4/6 results in decreased Rb
phosphorylation, which activates Rb’s cell cycle inhibitory function. However, many tumors do not respond to
these inhibitors or do so only transiently. Recent observations in patients and pre-clinical models indicate that
our understanding of the Rb pathway is not as complete as we previously thought. This may explain the variable
results of Cdk4/6 inhibitors in the clinic. The overall goal of this proposal is to gain a deeper structural, molecular,
and cellular understanding of the Rb pathway with the ultimate goal to help design new and improved therapeutic
strategies targeting this pathway in a broad range of cancer patients. Our first goal is to determine the core
mechanisms regulating the Cyclin D-Cdk4/6-Rb-E2F pathway, including how Cyclin D-Cdk4/6 phosphorylates
Rb and how previously unknown post-translational modifications regulate Rb and E2F activities. Our second
goal is to identify and investigate new functions of Rb pathway components, including new targets of Cyclin D-
Cdk4/6 kinases, new functions for Rb and its family members p107 and p130, and new regulatory mechanisms
controlling the concentration and activity of E2F transcription factors. Our third goal is to initiate the development
of strategies that target the Rb pathway in innovative ways, including molecules that inhibit Cyclin D-Rb
association, stimulate the tumor suppressor activity of p107 and p130, and manipulate E2F stability. T...

## Key facts

- **NIH application ID:** 10977262
- **Project number:** 3P01CA254867-03S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Seth Michael Rubin
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $87,061
- **Award type:** 3
- **Project period:** 2022-03-25 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977262

## Citation

> US National Institutes of Health, RePORTER application 10977262, Determining and targeting mechanisms controlling cancer cell division (3P01CA254867-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10977262. Licensed CC0.

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