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.

Overall NARRATIVE The Houston Center for Acquired Resistance Research (H-CARR) will act as the organizing entity for a multi- institutional, multi-disciplinary effort to detect acquired cisplatin resistance early in development and generate molecular and metabolic strategies for overcoming it. Investigators from Baylor College of Medicine and the University of Texas MD Anderson Cancer Center will investigate interactions between cancer cells, infiltrating immunocytes and neurons to both understand the critical drivers of cisplatin resistance in head and neck squamous cell carcinoma and develop precision oncology approaches to its clinical utilization in this deadly cancer and other similar solid tumors.