# Dissecting the interaction between DNA damage repair defects and the tumor microenvironment

> **NIH NIH DP5** · DANA-FARBER CANCER INST · 2021 · $442,500

## Abstract

PROJECT SUMMARY
Genomic analysis of high grade serous ovarian cancer (HGSC) has revealed that up to 50% of HGSCs harbor
a genomic alteration in a DNA damage repair (DDR) gene, mostly in the BRCA repair pathway. Functional
profiling of DDR capacity of patient derived HGSC organoids has revealed that over 60% of HGSCs harbor
defects in the stalled replication fork protection DDR pathway. Further analysis of these HGSC organoids
reveals that in patients who receive neoadjuvant chemotherapy, a tumor which initially had a replication fork
protection defect and was carboplatin sensitive can be induced by the neoadjuvant chemotherapy to undergo
replication fork stabilization and become carboplatin resistant. Transcriptional analysis of the post-neoadjuvant
fork stable organoids reveals that these cultures have undergone an epithelial-mesenchymal transition. Based
on these results, the hypothesis is that defects in the stalled replication fork protection DDR pathway are a
fundamental molecular defect in HGSC that when perturbed by treatment with neoadjuvant carboplatin can
lead to loss of the defect at the molecular level, alterations in the overall state of the tumor cells, and changes
in the way the tumor cells interact with the surrounding stroma and immune cells, all of which combine to
create a broadly therapy resistant tumor microenvironment. The research challenge I will pursue is to dissect
the evolving mechanisms by which tumor cells which originally harbor fork protection defects and are induced
to lose the defect interact with the surrounding stroma and immune cells and how these changing interactions
might be manipulated to prevent a deeply resistant tumor microenvironment. The work will utilize a novel
HGSC organoid co-culture system which will be highly innovative for the field because it will allow real time
assessment of the interactions between DDR defective or altered tumor cells and the surrounding normal cells
over time and treatment. Approach: The goal of Aim 1 is to generate growth conditions for co-cultures of fork
unstable platinum sensitive organoids with patient matched intra-tumoral stromal cells and all immune cells (T
cells, B cells, NK cells, dendritic cells, macrophages, and neutrophils). The goal of Aim 2 will be to generate
isogenic pairs of the organoids from Aim 1 that are fork stable and unstable and then study how the interaction
of the tumor cells with the surrounding stromal cells changes in the organoid co-culture system as the tumor
cells undergo selective fork stabilization. The goal of Aim 3 is to utilize the isogenic pairs of fork unstable and
stable organoids from Aim 2 in the co-culture system and determine how the interaction of the tumor cells with
the surrounding immune cells changes as the tumor cells undergo fork stabilization and how this may alter
response to immuno-oncologic agents. This work will have major impact in HGSC because it will help
understand the evolution of the tumor-normal cell interact...

## Key facts

- **NIH application ID:** 10260641
- **Project number:** 5DP5OD029637-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Sarah James Hill
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $442,500
- **Award type:** 5
- **Project period:** 2020-09-16 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260641

## Citation

> US National Institutes of Health, RePORTER application 10260641, Dissecting the interaction between DNA damage repair defects and the tumor microenvironment (5DP5OD029637-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10260641. Licensed CC0.

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