U54CA274321

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

The Univeristy Of Texas M.D. Anderson Cancer Center

TO PROVIDE AN ORGANIZATIONAL FOCUS AND STIMULUS FOR THE HIGHEST QUALITY CANCER RESEARCH THAT EFFECTIVELY PROMOTES INTERDISCIPLINARY CANCER RESEARCH AIMED TOWARD THE ULTIMATE GOAL OF REDUCING CANCER INCIDENCE, MORTALITY AND MORBIDITY. THE CANCER CENTER SUPPORT GRANT (CCSG) PROVIDES THE RESOURCES AND INFRASTRUCTURE TO FACILITATE THE COORDINATION OF INTERDISCIPLINARY PROGRAMS ACROSS A BROAD SPECTRUM OF RESEARCH FROM BASIC LABORATORY RESEARCH TO CLINICAL INVESTIGATION TO POPULATION SCIENCE. THE CCSG SUPPORTS SALARIES FOR SCIENTIFIC LEADERSHIP OF THE CENTER, SHARED RESOURCES FOR FUNDED CENTER INVESTIGATORS, CERTAIN ADMINISTRATIVE COSTS, PLANNING AND EVALUATION, AND DEVELOPMENTAL FUNDS FOR NEW RECRUITMENTS AND FEASIBILITY STUDIES.

93.397 - Cancer Centers Support Grants

National Cancer Institute (NCI) [HHS - NIH]

Houston, Texas 770304009 United States

Single Zip Code

Acquired Resistance to Therapy Network (ARTNet; U54 Clinical Trial Not Allowed) (RFA-CA-21-052)

Amendment Since initial award the total obligations have increased 333% from $1,237,322 to $5,352,094.