The Houston Center for Acquired Resistance Research (H-CARR)

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Principal Investigator: Jeffrey Nicholas Myers
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $238,959
Funding agency: National Cancer Institute

Overall SUMMARY
 Head and neck squamous cell carcinoma (HNSCC) remains a leading cause of cancer deaths worldwide
with ~500,000 cases/year. Cisplatin is the gold standard systemic agent for HNSCC. Cisplatin resistance, both
intrinsic and acquired, has been described in preclinical models and is frequently encountered in clinical practice;
when it occurs it is deadly. The overarching goal of H-CARR is to develop a robust biological understanding
of the key drivers of cisplatin resistance in HNSCC and develop the means of detecting it early in development
and overcoming it once it arises. We previously showed that: 1) cellular processing of cisplatin generated
metabolic stress is a critical driver of sensitivity and/or resistance and 2) coordinated genomic (TP53 mutation)
and transcriptomic (Nrf-2 activation) reprogramming is essential to organizing the metabolic response to cisplatin
generated stress. H-CARR brings together our biological and metabolic models of cisplatin resistance and our
translational capabilities to image tumor metabolism non-invasively and detect biological shifts using circulating
tumor cells (CTCs), to provide a comprehensive window into acquisition of cisplatin resistance as outlined in the
Projects listed below, supported by a robust administrative and analytical infrastructure organized into 3 Cores.
Project 1 will use state of the art metabolomic studies to identify the critical metabolic dependencies of
cisplatin resistant HNSCC, identify opportunities for effective metabolic inhibition and improve our understanding
of the cross-talk between the acquisition of cisplatin resistance and modulation of the tumor immune
microenvironment. Project 2 will explore the genomic and transcriptomic reprogramming required to sustain the
metabolic shifts which accompany development of resistance and interrogate how Nrf-2 dependent and
independent signaling drives resistance and enhanced distant metastasis through intrinsic cellular mechanisms
and paracrine signaling between tumor cells and adrenergic neurons. Project 3 will test whether the metabolic
reprogramming outlined in Project 1 is detectable via non-invasive imaging (hyperpolarized magnetic resonance
imaging) and whether the biological shifts outlined in Project 2 due to clonal extinction and expansion can be
detected using CTC analysis in patients undergoing cisplatin-based treatment.
 H-CARR has the potential to realize the full clinical utility of cisplatin by identifying acquisition of
resistance early during treatment and developing the means to overcome this and associated phenotypes such
as enhanced distant metastasis. Successful completion of the proposed experiments will generate the new
clinical standard for precision oncology approaches to clinical utilization of cisplatin in HNSCC and related upper-
aerodigestive tract cancers of the lung and esophagus and therefore have a major impact on cancer survival
worldwide.

Terms: <Acute><Adrenergic Agents><Adrenergic Drugs><Adrenergics><Algorithms><Amino Acids><Anti-EGFR Monoclonal Antibody><Anti-Epidermal Growth Factor Receptor Monoclonal Antibody><Antioncogene Protein p53><Biological><Biological Markers><Biomass><CDDP><Cancer Cause><Cancer Etiology><Cancers><Carbon><Cell Communication and Signaling><Cell Signaling><Cellular Tumor Antigen P53><Cessation of life><Cetuximab><Checkpoint inhibitor><Chronic><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><Citric Acid Cycle><Clinical><Clinical Trials><Cysplatyna><Data><Death><Dependence><Development><Dichlorodiammineplatinum><Distant Cancer><Distant Metastasis><Drugs><Esophageal Cancer><Esophagus Cancer><Extinction><FADH2><GPX2><GPX2 gene><Gastrointestinal Glutathione Peroxidase><Generations><Genetic Alteration><Genetic Change><Genetic defect><Genomics><Genotoxic Stress><Glutathione><Glutathione Peroxidase 2><Glycolysis><Goals><HNSCC><HPV><Head and Neck Squamous Cell Carcinoma><Human><Human Papilloma Virus><Human Papillomavirus><Image><Immune checkpoint inhibitor><Individual><Induction Therapy><Infectious Human Wart Virus><Infiltration><Infrastructure><Institution><Intracellular Communication and Signaling><Invaded><Investigators><Krebs Cycle><Link><MDACC><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Malignant Cell><Malignant Esophageal Neoplasm><Malignant Esophageal Tumor><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Esophagus><Malignant Tumor of the Lung><Malignant neoplasm of esophagus><Malignant neoplasm of lung><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Medicine><Metabolic><Metabolic stress><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Modality><Modeling><Modern Man><Molecular><Mutation><NEOADJ><NMR Imaging><NMR Tomography><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Neoplasm Circulating Cells><Neoplasm Metastasis><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nuclear Magnetic Resonance Imaging><Oncoprotein p53><P53><Paracrine Communication><Paracrine Signaling><Pathway interactions><Patients><Peyrone's Chloride><Peyrone's Salt><Pharmaceutical Preparations><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Platinum Diamminodichloride><Pre-Clinical Model><Preclinical Models><Production><Protein TP53><Pulmonary Cancer><Pulmonary malignant Neoplasm><Pyruvate><Regimen><Research><Research Personnel><Researchers><Resistance><Resistance development><Resistant development><Role><SCCHN><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Stress><TCA cycle><TP53><TP53 gene><TRP53><Technical Expertise><Testing><Time><Tricarboxylic Acid Cycle><Tumor Biology><Tumor Cell><Tumor Immunity><Tumor Protein p53><Tumor Protein p53 Gene><University of Texas M D Anderson Cancer Center><University of Texas MD Anderson Cancer Center><Upper aerodigestive tract cancer><Zeugmatography><afferent nerve><aminoacid><anti-tumor immunity><antitumor immunity><bio-markers><biologic><biologic marker><biological signal transduction><biomarker><cancer cell><cancer cell metabolism><cancer imaging><cancer immunity><cancer metabolism><cancer metastasis><cancer survival><chemotherapeutic agent><chemotherapy><circulating neoplastic cell><circulating tumor cell><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><clinical applicability><clinical application><clinical practice><college><collegiate><design><designing><developing resistance><developmental><drug/agent><early biomarkers><early detection biomarkers><early detection markers><experiment><experimental research><experimental study><experiments><gamma-L-Glu-L-Cys-Gly><gamma-L-Glutamyl-L-Cysteinylglycine><genome mutation><head and neck squamous carcinoma><head and neck squamous cell cancer><imaging><imaging study><immune check point inhibitor><immune microenvironment><immunogenic><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><improved><individual patient><individualized cancer care><individualized oncology><induction therapies><insight><lung cancer><malignancy><metabolic imaging><metabolism measurement><metabolomics><metabonomics><multidisciplinary><neoplasm/cancer><neoplastic cell><neuronal><non-invasive imaging><noninvasive imaging><novel><oesophageal cancer><oncologic imaging><oncology imaging><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><personalized oncology><precision cancer care><precision cancer medicine><precision oncology><prevent><preventing><prospective><protein p53><resistant><response><sensory nerve><social role><standard of care><targeted agent><technical skills><transcriptomics><translational opportunities><translational potential><tumor><tumor cell metabolism><tumor cell metastasis><tumor imaging><tumor immune microenvironment><tumor metabolism><tumor-immune system interactions><wart virus>