# Targeting replication stress to engage DNA sensing STING pathway derived anti-tumor immunity to improve the therapeutic outcomes in uterine cancer

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2024 · $511,431

## Abstract

Project Summary
Microsatellite stable (MSS)/mismatch repair proficient (MMRP) uterine cancers (UCs) represent approximately
two thirds (66%) of all UCs in The Cancer Genome Atlas (TCGA). The combination of pembrolizumab with
lenvatinib is currently the only FDA approved treatment for recurrent MSS/MMRP UCs, but adverse effects are
a major challenge in the clinic and a large population of patients do not respond to this regimen. There are
currently no FDA approved and no effective salvage therapies for patients with recurrent MSS/MMRP UC who
do not tolerate, do not respond or progress through pembrolizumab/lenvatinib. Notably, MSS/MMRP UCs are
characterized by genomic alterations associated with high degree of replication stress (RS); therefore, use of
DNA damage checkpoint kinase inhibitors such as WEE1 or ATR inhibitor can be therapeutically exploited to
induce tumor-selective synthetic lethality and modulate anti-tumor immunity, representing an appealing strategy
against these tumors. Furthermore, in our preliminary work, we have demonstrated that targeting the RS with
ATR or WEE1 in UCs leads to activation of the STING/TBK1/IRF3 pathway. Thus, we hypothesize that DNA
damage checkpoint kinase inhibitors will increase RS-associated DNA damage to engage DNA sensing STING
pathway activation to prime the immunologically “cold” MSS/MMRP UCs into “hot” tumors; combined DNA
damage targeting agents with immune checkpoint inhibitors (ICIs) can overcome tumor-associated
immunosuppression and lead to effective antitumor activity against MSS/MMRP UCs. We propose to test an
entirely novel strategy to extend the benefit of immunotherapy in MSS/MMRP UC by using DNA damage
checkpoint kinase inhibitors in combination with ICIs in both human and murine models of UC. In Aim 1, we
propose to characterize the immune effects of ATR and WEE1 inhibitors on human UC cell lines, patient-derived
organoid models and tumor specimens from the clinical trials of adavosertib and BAY1895344/copanlisib from
Projects 1 and 2 respectively. In Aim 2, we will assess the contribution of RS-targeting potentiated DNA sensing
STING pathway activation to the immune effect and therapeutic efficacy of WEE1 or ATR inhibition in vivo in
syngeneic models of UC, and in Aim 3, we will evaluate the anti-tumor immunity and therapeutic efficacy of
WEE1i or ATRi in combination with ICI in vivo in syngeneic models of UC. The overarching goal of this project
is to provide the mechanistic insights and important information to support initiation of clinical trials of effective
combinations DNA damage checkpoint inhibitors with ICI in patients with MSS/MMRP UC.

## Key facts

- **NIH application ID:** 10769258
- **Project number:** 1P01CA269021-01A1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Jean Zhao
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $511,431
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769258

## Citation

> US National Institutes of Health, RePORTER application 10769258, Targeting replication stress to engage DNA sensing STING pathway derived anti-tumor immunity to improve the therapeutic outcomes in uterine cancer (1P01CA269021-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10769258. Licensed CC0.

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