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Precision Imaging of Cardiotoxicity: Metabolic MR Biomarkers for Pathophysiology, Early Detection, and Cardioprotection Effect Monitoring

Award Number: R01CA316800
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/12/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Precision Imaging of Cardiotoxicity: Metabolic MR Biomarkers for Pathophysiology, Early Detection, and Cardioprotection Effect Monitoring - ABSTRACT Cardiotoxicity remains a leading cause of morbidity and mortality among cancer survivors and a major barrier to safe cancer therapy. Current diagnostic strategies detect late functional decline rather than the early biological alterations that precede irreversible injury. Widely used anthracyclines, such as doxorubicin, induce cardiotoxicity by directly injuring mitochondria, leading to impaired oxidative metabolism, suppression of pyruvate dehydrogenase (PDH) activity, depletion of high-energy phosphate reserves, and diversion of glucose metabolism toward lactate and alanine production via lactate dehydrogenase (LDH) and alanine aminotransferase (ALT). In contrast, immune checkpoint inhibitors (ICIs) trigger cardiotoxicity through immune activation, causing myocarditis with inflammatory infiltration, cytokine-mediated metabolic stress, and secondary mitochondrial dysfunction. Despite these distinct initiating mechanisms, both converge on a shared metabolic phenotype of impaired glucose oxidation, lactate shunting, ALT dysregulation, and depletion of the phosphocreatine/creatine kinase (PCr/CK) energy system. These energetic disturbances drive progressive ventricular dysfunction, underscoring the need for imaging biomarkers that detect mechanistic alterations before structural and functional decline. This project establishes a co-clinical imaging framework integrating preclinical models with early human studies to define noninvasive biomarkers of therapy-induced cardiotoxicity. We will combine hyperpolarized (HP) 13C MRI to quantify PDH, LDH, and ALT fluxes; 31P MR spectroscopic imaging to measure phosphocreatine/ATP ratios; and proton MRI to assess cardiac structure and function. Together, these complementary modalities will characterize the temporal evolution of metabolic and energetic derangements in anthracycline- and ICI-induced cardiotoxicity. Animal models are essential for establishing the mechanistic basis and temporal evolution of therapy-induced cardiotoxicity in a controlled setting before translation to patients. These preclinical studies provide the biological foundation for interpreting imaging biomarkers in subsequent human studies. The resulting mechanistic signatures will be translated into patients to establish the feasibility, reproducibility, and clinical relevance of these early-detection biomarkers. We will also evaluate whether these imaging biomarkers sensitively monitor the cardioprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i). Originally developed for diabetes and now widely used for heart failure and chronic kidney disease, SGLT2i improve myocardial energetics, reduce oxidative stress, and attenuate fibrosis and inflammation. By integrating metabolic and energetic imaging across preclinical and clinical studies, this project will establish clinically translatable biomarkers for the early detection and therapeutic monitoring of cancer therapy–associated cardiotoxicity and provide a mechanistic framework for evaluating cardioprotective interventions.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $635,782 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	000	1	8/12/2026	NEW	$635,782
														Subtotal = $635,782

Grand Total All Awards = $635,782

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Precision Imaging of Cardiotoxicity: Metabolic MR Biomarkers for Pathophysiology, Early Detection, and Cardioprotection Effect Monitoring

Award Number: R01CA316800

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/12/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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