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Principal Investigator: James A Bankson
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $1
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Head and neck squamous cell carcinoma (HNSCC) remains a leading cause of cancer deaths worldwide.
Genotoxic agents, including radiation therapy (RT) and cisplatin (CDDP), are treatments that damage cellular
DNA. RT and CDDP are the current standard of care in multiple solid tumors, including HNSCC. CDDP is the
most commonly used chemotherapeutic agent in HNSCC proving superior to novel targeted agents in recent
large randomized trials. Despite this, high rates of treatment failure persist in patients who develop resistance
following this toxic chemotherapy. Treatment failure is uniformly fatal. However, no robust predictors of
acquired cisplatin resistance or tumor response exist. Given this critical unmet need, we have focused our efforts
on the assessment of tumor response using minimally invasive quantitative imaging (hyperpolarized magnetic
resonance imaging; HP-MRI) while patients are undergoing therapy. We showed that CDDP and other genotoxic
agents trigger measurable fluctuations in tumor cell metabolism detectable through HP-MRI with [1-13C]-pyruvate
in real time (confirmed by conventional biochemical assays). Genotoxic stress suppresses the apparent rate of
pyruvate conversion into lactate (kPL) via lactate dehydrogenase (LDH) in a manner that correlates with anti-
tumor effectiveness. We therefore hypothesize that changes in kPL provide unique insight into metabolic
changes induced by cisplatin that can be used to optimize response to therapy in HNSCC.
In Aim 1, we will characterize baseline HP-MRI parameters such as kPL across the spectrum of HNSCC
subtypes and validate the relationship between CDDP and associated shifts in carbon flux. We will also identify
metabolomic differences in HNSCC models that affect baseline values of metabolic imaging biomarkers and
modulate apparent changes induced by cisplatin. In Aim 2, we will integrate the dose-response data from Aim 1
to develop a predictive model of response to CDDP based on metabolic imaging parameters. We will use a
simple algorithm to adjust therapeutic dose based on HP-MRI data in animal models of HNSCC to maximize
tumor growth delay, and test whether thresholds suggestive of strong response can be used to select the more
effective treatment regimen when multiple regimens are tested in parallel. In Aim 3, we will conduct a first-in-
human evaluation of changes in HP-MRI to detect shifts in carbon flux following CDDP in HNSCC patients. We
will correlate changes in metabolic imaging parameters with the baseline metabolic phenotype of tumors as
determined from metabolomic analysis and direct measurements of tumor LDH. Successful completion of this
study will establish HP-MRI as a non-invasive imaging modality able to predict response to treatment,
which will be a noteworthy first step towards a precision oncology approach that we have been seeking for nearly
half a century. Thus, the proposed research is relevant to the part of the NIH’s mission that pertains to developing
and applying fundamental knowledge that will help to reduce the burdens of human illness and addresses directly
the recently published “Notice of Special Interest: Precision Imaging of Oral Lesions” (NOT-DE-21-010).
Terms: <Address><Affect><Algorithms><Animal Model><Animal Models and Related Studies><Assay><Bioassay><Biochemical><Biological Assay><Biology><Biopsy><CDDP><Cancer Cause><Cancer Etiology><Carbon><Cellular injury><Cessation of life><Characteristics><Chemicals><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clinical Trials><Coenzymes><Cysplatyna><DNA><DNA Damage><DNA Injury><Data><Data Analyses><Data Analysis><Death><Deoxyribonucleic Acid><Development><Dichlorodiammineplatinum><Dihydronicotinamide Adenine Dinucleotide><Diphosphopyridine Nucleotide><Dose><EC 1.1.1.27><Effectiveness><Enzyme Cofactors><Evaluation><Exposure to><Failure><Feedback><Genotoxic Stress><Genotoxins><Glycolysis><Goals><Grant><HNSCC><HPV associated HNSCC><HPV driven HNSCC><HPV driven head and neck cancer><HPV(+) HNSCC><HPV(+) head and neck squamous cell carcinoma><HPV+ HNSCC><HPV+ head and neck cancers><HPV-associated head and neck cancer><HPV-associated head and neck squamous cell carcinoma><HPV-positive HNSCC><HPV-positive head and neck cancers><HPV-related HNSCC><HPV-related head and neck squamous cell carcinoma><Head and Neck><Head and Neck Cancer><Head and Neck Carcinoma><Head and Neck Squamous Cell Carcinoma><Head and neck structure><Heterogeneity><Heterograft><Heterologous Transplantation><Human><Human papillomavirus driven HNSCC><Human papillomavirus driven head and neck cancer><Image><In Vitro><Individual><Knowledge><L-Lactate Dehydrogenase><L-Lactic Acid Dehydrogenase><Lactate Dehydrogenase><Link><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Malignant Head and Neck Neoplasm><Measurable><Measurement><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Metabolic><Metabolic Pathway><Mice><Mice Mammals><Mission><Modeling><Modern Man><Murine><Mus><Mutagens><NAD-Lactate Dehydrogenase><NIH><NMR Imaging><NMR Tomography><Nadide><National Institutes of Health><Nicotinamide adenine dinucleotide><Nicotinamide-Adenine Dinucleotide><Non-Invasive Detection><Noninvasive Detection><Nuclear Magnetic Resonance Imaging><Oxidation-Reduction><PDX model><Patient Recruitments><Patient derived xenograft><Patients><Peyrone's Chloride><Peyrone's Salt><Phosphates><Platinum Diamminodichloride><Pre-Clinical Model><Preclinical Models><Public Health><Publishing><Pyruvate><Radiation therapy><Radiotherapeutics><Radiotherapy><Randomization trial><Reaction><Recycling><Redox><Regimen><Research><Resistance><Resistance development><Resistant development><Resolution><SCCHN><Selection Criteria><Sensitivity and Specificity><Series><Shunt><Shunt Device><Solid Neoplasm><Solid Tumor><Testing><Therapeutic><Time><Toxic effect><Toxicities><Translational Research><Translational Science><Treatment Effectiveness><Treatment Failure><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tumor Burden><Tumor Cell><Tumor Load><Tumor Volume><United States><United States National Institutes of Health><Work><Xenograft><Xenograft procedure><Xenotransplantation><Zeugmatography><cancer cell metabolism><cancer metabolism><cell damage><cell injury><cell killing><cellular damage><chemotherapeutic agent><chemotherapy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><clinical applicability><clinical application><clinical relevance><clinically relevant><coenzyme analog><computer based prediction><damage to cells><data interpretation><design><designing><developing resistance><developmental><drug detection><drug testing><effective therapy><effective treatment><first in man><first-in-human><genotoxic agent><head and neck squamous carcinoma><head and neck squamous cell cancer><head/neck cancer><human papilloma virus+ head and neck squamous cell carcinoma><human papillomavirus associated head and neck cancer><human papillomavirus associated head and neck squamous cell carcinoma><human papillomavirus driven head and neck squamous cell carcinoma><human papillomavirus induced head and neck squamous cell carcinoma><human papillomavirus positive HNSCC><human papillomavirus positive head and neck cancers><human papillomavirus positive head and neck squamous cell carcinoma><human papillomavirus related head and neck squamous cell carcinoma><image-based method><imaging><imaging biomarker><imaging marker><imaging method><imaging modality><imaging probe><imaging-based biological marker><imaging-based biomarker><imaging-based marker><in vivo><individual patient><individualized cancer care><individualized management><individualized oncology><individualized patient management><injury to cells><innovate><innovation><innovative><inorganic phosphate><insight><interest><lactic acid dehydrogenase><malignant head and neck tumor><metabolic imaging><metabolic phenotype><metabolism measurement><metabolomics><metabonomics><metabotype><minimally invasive><model of animal><mouth lesion><neoplastic cell><non-invasive imaging><noninvasive imaging><novel><oral HPV-positive HNSCC><oral HPV-positive head and neck cancers><oral human papillomavirus positive head and neck cancers><oral human papillomavirus positive head and neck squamous cell carcinoma><oral lesion><oxidation><oxidation reduction reaction><participant recruitment><patient derived xenograft model><personalized clinical management><personalized disease management><personalized management><personalized oncology><pre-clinical trial><precision cancer care><precision cancer medicine><precision management><precision oncology><preclinical trial><predict responsiveness><predicting response><predictive modeling><prospective><quantitative imaging><radiation treatment><randomized trial><resistant><resolutions><response><response to therapy><response to treatment><shunts><standard of care><success><targeted agent><therapeutic response><therapy failure><therapy optimization><therapy response><transcriptomics><translation research><translational investigation><treatment optimization><treatment response><treatment responsiveness><treatment with radiation><tumor><tumor cell metabolism><tumor growth><tumor metabolism><xeno-transplant><xeno-transplantation>