# "Optimizing synthetic lethality in high-grade serous ovarian cancer"

> **NIH NIH P50** · JOHNS HOPKINS UNIVERSITY · 2021 · $256,092

## Abstract

PROJECT 2 PROJECT SUMMARY
 Ovarian high-grade serous cancer (HGSC) is the most lethal gynecological malignancy. More than 80% of
HGSC patients recur after standard chemotherapy. We have identified a novel and highly active genotoxic
therapy by co-inhibiting poly-ADP ribose polymerase (PARP) and ATR checkpoint kinase. Combination PARP
inhibition with ATR inhibition (PARPi-ATRi) synergizes to specifically target and kill ovarian HGSCs harboring
common HGSC-associated alterations, e.g. homologous recombination (HR) deficiency and Cyclin E
overexpression. Our preliminary studies show that PARPi-ATRi in combination is especially effective in killing
tumor cells with these alterations and even causing regression of HR-deficient and Cyclin E overexpressing
ovarian HGSCs. In the clinic, PARP inhibition (PARPi) treatment alone for ovarian cancer alone results in partial
tumor regression and rarely complete responses with the ultimate emergence of drug resistance. This proposal
addresses this urgent clinical need by using a potent new combination treatment to convert partial responses
with PARPi monotherapy into complete and durable tumor regression.
 For these studies, we have developed: 1) >60 PDX models representing the clinically most common and
challenging conditions to treat including: HR-deficient, PARPi-resistant and Cyclin E overexpressing ovarian
HGSCs with differing platinum sensitivities, 2) a novel PARPi tracer that will be tested as a predictive and
pharmacodynamic marker to guide patient selection for PARPi therapies, 3) advanced proteomic methods to
detect both global-tumor and replication fork-specific responses to treatment. We hypothesize that dual inhibition
of PARP and ATR will increase the frequency of complete tumor regression in ovarian cancer compared to
PARPi monotherapy. The proposed studies herein will test the efficacy of PAPR inhibitor (PARPi, olaparib), by
combination with ATR inhibitor (ATRi, AZD-6738) in the first clinical trial in ovarian cancer supported by our
preclinical data. Secondly, we will identify dosing schedule strategies to minimize drug toxicity without
compromising efficacy for PARPi-ATRi in PDX models. Combination PARPi-ATRi has shown efficacy and
tolerability in early phase IB trials, but ways to decrease toxicity are important to optimize quality of life for these
patients. Finally, we will perform genomic and proteomic studies to identify biomarkers of PARPi-ATRi response
for evaluation in future clinical trials. Our Hopkins–PENN SPORE team is comprised of: expert clinical trialists,
translational scientists with preclinical models and drug optimization expertise, molecular biologists with
expertise in DNA replication stress, SPORE Cores such as Pathology that will promote optimal patient tissue
procurement and processing and Biostats to oversee data analysis. Thus, our team is well positioned for success
with realizing Project 2 goals.

## Key facts

- **NIH application ID:** 10222605
- **Project number:** 5P50CA228991-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** FIONA SIMPKINS
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $256,092
- **Award type:** 5
- **Project period:** 2018-09-18 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222605

## Citation

> US National Institutes of Health, RePORTER application 10222605, "Optimizing synthetic lethality in high-grade serous ovarian cancer" (5P50CA228991-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10222605. Licensed CC0.

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