# Targeting molecular vulnerabilities of ovarian cancer

> **NIH NIH K08** · DANA-FARBER CANCER INST · 2020 · $253,377

## Abstract

PROJECT SUMMARY
 Genomic analysis suggests that up to 50% of High Grade Serous Ovarian Cancers (HGSCs) harbor a
genomic alteration that might confer a DNA damage repair defect, making therapies that target such defects
potential treatment options. There is no method to predict which patients will respond to such therapies, which
is a major problem in the field. Preliminary data indicate that patient derived HGSC organoids may be a faithful
model system in which to perform functional assays to predict patient therapeutic response. Data from a limited
analysis of HGSC organoids suggest that stalled replication fork protection defects are more common than
homologous recombination defects in HGSC and that more patients may benefit from the wider array of
therapies available to target such defects, including carboplatin, gemcitabine, ATR, WEE1, and CHK1
inhibitors. The goal of this mentored research career development proposal is to utilize patient derived HGSC
organoid cultures to understand the prevalence, mechanisms, and therapeutic relevance of stalled replication
fork protection defects in HGSC. The proposed research studies encompass multiple disciplines including
molecular biology, DNA sequencing, and animal modeling which will help investigate the role of stalled
replication fork protection defects in HGSC and also provide a well-rounded career development strategy for
becoming scientifically independent through execution of the following specific aims:
Specific Aim 1: Assess the prevalence of fork protection defects in HGSC and whether fork protection defects
predicted by HGSC organoid functional assays lead to therapeutic sensitivity to carboplatin and ATR, WEE1,
and CHK1 inhibitors. This will be accomplished by generating organoids from patients being treated with
carboplatin and ATR, WEE1, and CHK1 inhibitors, performing functional assays to assess stalled fork
protection capacity and therapeutic sensitivity of the organoids in parallel to sequencing analysis, and
comparing organoid and patient outcomes.
Specific Aim 2: Uncover mechanisms leading to fork instability in the organoids and whether different
mechanisms of fork protection defects lead to differing sensitivities to the above agents. This will be
accomplished using molecular and cellular biology analysis of specific pathways in the organoids.
Specific Aim 3: In vivo validation of in vitro mechanisms of stalled replication fork protection defects leading to
therapeutic responses in organoid xenograft models of HGSC. This will be accomplished by generating mouse
models using select organoids from aim 2 and testing them for therapeutic responses to agents used in aim 2.
 The career development award candidate is an MD/PhD clinically trained in anatomic pathology. The
proposed research will occur at Dana-Farber Cancer Institute under the mentorship of Dr. Alan D'Andrea. The
candidate will utilize the additional training provided by this award to facilitate her ultimate career goal of...

## Key facts

- **NIH application ID:** 9976800
- **Project number:** 1K08CA241093-01A1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Sarah James Hill
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $253,377
- **Award type:** 1
- **Project period:** 2020-03-01 → 2020-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976800

## Citation

> US National Institutes of Health, RePORTER application 9976800, Targeting molecular vulnerabilities of ovarian cancer (1K08CA241093-01A1). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/9976800. Licensed CC0.

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