# Overcoming cisplatin resistance by targeting fatty acid metabolism

> **NIH NIH R03** · BAYLOR COLLEGE OF MEDICINE · 2020 · $166,936

## Abstract

ABSTRACT
 Chemotherapy is a critical tool in reducing locoregional recurrence and distant metastasis in
patients with advanced oral cavity squamous cell carcinoma (OCSCC). Although an old drug,
cisplatin forms the backbone of chemotherapy regimens for OCSCC in the United States. Since
OCSCC cisplatin response is highly variable, it is critical to develop novel means of overcoming
cisplatin resistance. Acquisition of “high-risk” TP53 mutations is a critical driver of OCSCC survival
and cisplatin resistance; however, mutations of TP53 cannot be effectively targeted directly. Our
preliminary data indicate, that targeting of lipid metabolism, could overcome cisplatin resistance
associated with “high-risk” TP53 mutations.
 Loss of p53 function through mutation: 1) impairs mitochondrial reserve capacity, 2)
increases glycolytic flux and 3) increases cellular adaptation to oxidative stress. These effects
occur in parallel with enhanced resistance to cisplatin. Fatty acid oxidation (FAO) and fatty acid
synthesis (FAS) are critical drivers of the cellular oxidative stress response since they are
responsible for a large portion of reducing equivalent (NADH, NADPH, FADH2) generation and/or
utilization. In Aim 1 we will test the impact of high-risk TP53 mutations on the FAO/FAS ratio and
evaluate the relative effectiveness of FAO inhibitors in improving cisplatin response in high-risk
TP53 mutations.
 In Aim 2 we will use a parallel approach to TP53 mutant tumors also predicated on lipid
metabolism. Ferroptosis (programmed cell death) is activated by oxidative stress and dependent
on lipid peroxidation. We found that ferroptosis agonists can generate cell death in both wild-type
and mutant TP53 OCSCC. In this Aim we will test whether ferroptosis agonists can overcome
cisplatin resistance associated with “high-risk” TP53 mutations in cell lines and PDX tumors.
 Despite a continued search for more effective alternatives, cisplatin remains the mainstay
systemic agent for use in advanced OCSCC. Until such time as other agents demonstrate clear
and convincing superiority, it is imperative that we develop more effective strategies which can
overcome cisplatin resistance. These strategies must also take into account the overwhelming
impact of TP53 mutations on OCSCC response to treatment. In the current proposal, we leverage
substantial preliminary data regarding metabolic targeting and propose to utilize an approach
predicated on fatty acid metabolism which we believe addresses both aspects of this deadly
disease.

## Key facts

- **NIH application ID:** 9980866
- **Project number:** 5R03DE028858-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** VLAD C SANDULACHE
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $166,936
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980866

## Citation

> US National Institutes of Health, RePORTER application 9980866, Overcoming cisplatin resistance by targeting fatty acid metabolism (5R03DE028858-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9980866. Licensed CC0.

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