# Understanding Metabolic Reprogramming in Platinum Resistant Ovarian Cancer

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2023 · —

## Abstract

PROJECT SUMMARY
This Collaborative Merit Award application (CMA), consisting of three projects (CMA1-3), addresses a critical
challenge in the clinical management of ovarian cancer. The most common and most lethal subtype of ovarian
cancer is high-grade serous ovarian carcinoma (HGSOC). Standard treatment for HGSOC combines surgical
cytoreduction with platinum-based chemotherapy. The treatment is initially successful in achieving remission.
However, cancer recurs in most women. Patients with recurrent disease may continue to respond to additional
rounds of platinum but will ultimately develop platinum resistance (PtR). At that point, the tumor is typically
resistant to other treatment strategies. The key to increasing survival in HGSOC is to prevent the development
of PtR or identify alternative means of targeting resistant tumors. The main goal of this interdisciplinary and
collaborative project is to identify novel targets and biomarkers of therapeutic efficacy for HGSOC. This requires
a better understanding of the mechanisms that either select for, or promote transformation of, HGSOC cells to
an aggressive, therapy-resistant phenotype. While previous studies on PtR have focused on DNA repair
pathways or altered membrane transporters, new concepts support the hypothesis that a key contributor to PtR
is the reprogramming of cancer cells into a less differentiated and metabolically adaptable state. This
collaborative proposal by three established ovarian cancer researchers will leverage their interdisciplinary
expertise and rich resources to define new molecular mechanisms of PtR in ovarian cancer. CMA1 will utilize
deep imaging to define clinically-relevant biomarkers of PtR while digital spatial profiling and systems biology
will be used to identify molecular pathways underlying PtR. Preclinical immunocompetent mouse models will be
used to test potential targeted therapies discovered in CMA1,2&3. CMA2 will study metabolic adaptation
associated with the emergence of PtR focusing on a shift to fatty acid oxidation in resistant HGSOC cells and
tumors. CMA2 will use resources shared with CMA1&3 and cellular biology and novel single cell metabolic
imaging to define unique metabolic dependencies of PtR HGSOC. As resistant tumors are highly susceptible to
death induced by oxidized lipid membranes, mechanisms of ferroptosis will be examined in PtR models treated
with novel metabolism targeting agents, which will be tested together with CMA1. CMA3 will define the emergent
de-differentiated phenotype in recurrent HGSOC through transcriptomic analysis of patient tumors collected at
various stages of disease progression. By defining molecular pathways that lead to cellular de-differentiation,
we will reveal new vulnerabilities that can be therapeutically exploited using small molecules, kinase inhibitors,
and cell-based immune therapy approaches Multi-omics data, patient derived organoids, and PDX models will
provide valuable shared resource for collaborat...

## Key facts

- **NIH application ID:** 10485428
- **Project number:** 1I01BX006012-01
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Daniela E Matei
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10485428

## Citation

> US National Institutes of Health, RePORTER application 10485428, Understanding Metabolic Reprogramming in Platinum Resistant Ovarian Cancer (1I01BX006012-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10485428. Licensed CC0.

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