# Quantification of cisplatin sensitivity and resistance using metabolic imaging and circulating tumor cell (CTC) biomarkers

> **NIH NIH U54** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $262,242

## Abstract

PROJECT 3 SUMMARY
Cisplatin (CDDP) remains the gold-standard for chemotherapeutic treatment for multiple solid tumors, including
head and neck squamous cell carcinoma (HNSCC). High rates of treatment failure result from the development
of acquired resistance following this relatively toxic chemotherapy. Despite the frequent use of CDDP, no robust
predictors of tumor response or development of acquired resistance exist. Treatment failure is uniformly fatal.
Given the critical unmet need for predictors of tumor response and acquired resistance, we have focused our
efforts on the assessment of tumor response with minimally invasive imaging (hyperpolarized magnetic
resonance imaging; HP-MRI) and detection of biological shifts in circulating tumor cells (CTCs) while patients
are undergoing cisplatin-based therapy. We have shown that CDDP and other genotoxic agents trigger
measurable fluctuations in tumor cell metabolism detectable by both conventional biochemical assays and HP-
MRI with [1-13C]-pyruvate. The recycling of key coenzymes in several reductive metabolic pathways links the
effects of genotoxic stress to carbon flux from pyruvate into lactate via lactate dehydrogenase (LDH). We
previously showed that genotoxic agents alter the intracellular redox state, shift pyruvate/lactate metabolism,
and suppress the apparent rate of pyruvate conversion to lactate (kPL) in a manner that correlates with anti-tumor
effectiveness. Genomic and transcriptomic analysis of regulatory shifts associated with the acquisition of cisplatin
resistance in CTCs will re-enforce the imaging-based quantification of cisplatin sensitivity and resistance. Based
on these preliminary data, we hypothesize that metabolic reprogramming driven by Nrf-2 in cisplatin-
resistant HNSCC is detectable using a combination of non-invasive imaging of carbon flux (kPL- via HP-
MRI) and scCTC analysis. To assess this premise, we will use well-characterized preclinical models of HNSCC
that are sensitive and resistant to cisplatin. Alterations in glycolytic metabolism will be measured at baseline and
following cisplatin administration through hyperpolarized imaging and biochemical assays. These measurements
will be validated with biochemical assays in vitro and in vivo (Aim 1). We will also measure treatment response
in HNSCC patients relative to alterations in tumor kPL by acquiring HP-MRI data prior to and following induction
chemotherapy (Aim 2). Biological confirmation will be performed in CTCs to identify biomarkers associated with
cisplatin resistance through genomic and transcriptomic analysis. Successful completion of this study will
establish HP-MRI as a minimally invasive imaging approach to characterize relative tumor resistance to cisplatin
and provide real-time feedback to optimize treatment. CTC biomarker analysis will provide critical biological
support for the imaging findings. This work has the potential to change the basis for clinical decision-making
regarding the use of cis...

## Key facts

- **NIH application ID:** 10917411
- **Project number:** 5U54CA274321-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** STEPHEN Y LAI
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $262,242
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917411

## Citation

> US National Institutes of Health, RePORTER application 10917411, Quantification of cisplatin sensitivity and resistance using metabolic imaging and circulating tumor cell (CTC) biomarkers (5U54CA274321-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10917411. Licensed CC0.

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