# Targeting Replication Stress and DNA Damage Response in Uterine Cancer

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2024 · $2,971,802

## Abstract

PROJECT SUMMARY
Uterine cancer (UC) incidence and death rates are both significantly increasing in the United States. Most UCs
are endometrial cancers which arise from the inner lining of the uterus and are defined by several different
histologic subtypes, the most common of which is endometrioid. Additionally, survival outcomes are worse for
black women. Because of the worsening survival of women with advanced and relapsed endometrial cancer,
this P01 grant is focused on targeting replication stress (RS) in order to improve therapeutic outcomes in these
patients. RS is defined as the slowing or stalling of the replication fork progression during DNA synthesis and is
widely recognized as a significant cause of genomic instability and a critical feature of cancer cells. This P01
grant investigates 3 different strategies for targeting RS in UC with the goal of translating these into effective
salvage therapies for women with advanced/relapsed UC. We have assembled a team of internationally
recognized researchers from the Dana-Farber Cancer Institute and the Brigham and Women’s Hospital, both in
Boston MA, with multidisciplinary expertise in UC, DNA repair and RS, immunotherapy, preclinical models,
biostatistics, computational biology, gynecologic pathology, drug development and clinical trials. This P01 grant
is being led by Drs. Panagiotis Konstantinopoulos, Joyce Liu, and Ursula Matulonis who are recognized
international leaders in the field of gynecologic cancer and endometrial cancer research.
This P01 grant consists of 3 Projects and 4 Cores. The leadership team for each Project is comprised of paired
investigators with complementary expertise in basic science and clinical/translational research. Project 1 focuses
on studying the mechanism of WEE1 inhibition in recurrent USC or p53-mutated UCs and the correlation of
WEE1 activity with functional and immunohistochemical (IHC) measures of RS. Based upon the results of a
clinical trial of the WEE1 inhibitor adavosertib which previously demonstrated significant clinical activity in USCs,
this project leverages a collection of patient-derived xenografts (PDXs), patient-derived organoids (PDOs), and
genetically engineered mouse models (GEMMs) of p53-mutated/null endometrial cancer to examine the effects
of WEE1 inhibition on functional and IHC measures of RS in the in vitro and in vivo setting. Additionally, through
a biopsy-driven investigator-initiated protocol of the WEE1 inhibitor ZN-c3 in USC, Project 1 will examine the
effects of WEE1 inhibition on measures of RS in co-clinical PDOs and correlation of these measures with clinical
activity. Project 2 focuses on the hypothesis that inhibition of the PI3K pathway can increase RS and therefore
create synergy with ATR inhibitors. In previously performed PRISM and CRISPR screens, inhibition of PI3K
signaling together with ATR inhibition was identified as potentially synergistic and subsequent experiments have
demonstrated synergism between the PI3K ...

## Key facts

- **NIH application ID:** 10769255
- **Project number:** 1P01CA269021-01A1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Panagiotis Konstantinopoulos
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,971,802
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769255

## Citation

> US National Institutes of Health, RePORTER application 10769255, Targeting Replication Stress and DNA Damage Response in Uterine Cancer (1P01CA269021-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10769255. Licensed CC0.

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