# BCCMA: Overcoming chemoresistance in ovarian cancer: Identification and validation of biomarkers and targetable drivers of platinum resistance

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2024 · —

## Abstract

This Collaborative Merit Award application (CMA), consisting of three projects (CMA1-3), addresses a critical
challenge in the clinical management of ovarian cancer (OC). The most common and lethal subtype of OC is
high-grade serous ovarian carcinoma (HGSOC). Standard treatment for HGSOC combines surgical
cytoreduction with platinum-based chemotherapy. Patients diagnosed with HGSOC often suffer from disease
relapse associated with the emergence of chemotherapy resistance. The clinically necessary key to increasing
survival in HGSOC is to prevent the development of platinum resistance (PtR) or identify alternative means of
targeting PtR 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
result in transformation of HGSOC cells to an aggressive, therapy-resistant phenotype. Increasing evidence
supports 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 OC researchers
will leverage their interdisciplinary expertise and rich resources to define new mechanisms of resistance in
OC. CMA1 will use digital spatial profiling and systems biology to provide a holistic understanding of PtR as well
as prioritize cell-intrinsic and microenvironmental clinically relevant underlying molecular pathways. Unique
preclinical immunocompetent mouse models and co-culture models will be used to study the role of the tumor
microenvironment in PtR. CMA2 will study metabolic adaptation associated with the emergence of PtR focusing
on a shift to fatty acid oxidation in PtR HGSOC 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 PtR 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
with CMA1. CMA3 will explore the reprogramming of recurrent HGSOC cells into more dedifferentiated tumor
subpopulations with neuroendocrine (NE)-like features. Mounting evidence in other tumors suggest progression
to a NE-like state results in therapy resistance - a concept yet to be explored in OC. To identify NE-like cells in
OC, the transcriptome, proteome, gene vulnerability, and drug sensitivity landscape of matched patient tumors
and model systems will be evaluated for the emergence of NE-like cells under chemotherapeutic pressures.
Existing drug dependency databases will be mined for identification of druggable targets in NE-like cells. Drugs
effective against these cells will be tested alone or in combination as targeted therapy for PtR OCs utilizing
patient derived organoid and xenograft models. Hallmarks of NE-like cells incl...

## Key facts

- **NIH application ID:** 10832497
- **Project number:** 5I01BX006020-02
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** SANDRA ORSULIC
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832497

## Citation

> US National Institutes of Health, RePORTER application 10832497, BCCMA: Overcoming chemoresistance in ovarian cancer: Identification and validation of biomarkers and targetable drivers of platinum resistance (5I01BX006020-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10832497. Licensed CC0.

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