# Proteogenomic studies aimed at understanding ovarian tumor responses to agents targeting the DNA damage response and translating this knowledge into clinical benefit

> **NIH NIH U01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $811,228

## Abstract

Project Summary/Abstract
 Epithelial ovarian cancer (EOC), the most lethal gynecological malignancy, is diagnosed in more than
225,000 women worldwide each year, with most patients presenting with advanced-stage, high-grade serous
ovarian cancers (HGSOC). Despite improvements in surgical and chemotherapeutic approaches, overall mor-
tality has not changed significantly for decades. Standard of care involves surgical debulking plus adju-
vant/neoadjuvant combination chemotherapy with platinum compounds and taxanes.
 Platinum compounds damage DNA by inducing intra- and inter-strand cross-links (ICL) between purine ba-
ses. ICL repair depends on both Fanconi anemia and BRCA proteins, which are required for homologous re-
combination. EOC is one of the most chemo-sensitive epithelial tumors, with initial response rates of ~75% to
platinum-based chemotherapy. The striking platinum sensitivity of EOC tumors is thought to be related to their
HRD. Unfortunately, 80-90% of patients suffer relapse and develop drug-resistant disease. Moreover, ~20% of
patients have platinum-refractory disease at diagnosis. Thus, there are crucial unmet clinical needs for
methods to predict platinum responsiveness of EOCs, and for treatments that can be used either alone or in
combination with platinum compounds to overcome resistance. The goals of our PTRC are to enhance our
ability to predict which EOCs will respond to DNA-damaging platinum therapy, to understand mechanisms of
resistance, and to identify potential new drug targets in resistant disease to point to desperately-needed new
therapeutic approaches for these patients.
 Our Proteogenomic Translational Research Center will perform proteo-genomic analyses of EOC preclini-
cal models (patient-derived xenografts and cell lines) pre- and post-treatment with platinum to add to and help
prioritize potential predictive protein targets of platinum response that have been implicated in the literature. In
our Clinical Arm, we will use targeted multiple reaction monitoring (MRM) mass spectrometry-based assays to
quantify potential predictive protein targets in tumor specimens obtained through NCI-funded trials, to test their
association with response to therapy. In addition, there is an imperfect and incompletely understood overlap in
tumor responses between platinum and PARP inhibitors (PARPi); thus, in an exploratory sub-aim, we will de-
termine which proteogenomic correlates of platinum response are also associated with response to PARPi
(e.g. based on underlying defects in homologous recombination (HR)-mediated DNA repair).

## Key facts

- **NIH application ID:** 10167644
- **Project number:** 5U01CA214114-05
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Michael Birrer
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $811,228
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167644

## Citation

> US National Institutes of Health, RePORTER application 10167644, Proteogenomic studies aimed at understanding ovarian tumor responses to agents targeting the DNA damage response and translating this knowledge into clinical benefit (5U01CA214114-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10167644. Licensed CC0.

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