Yale Head and Neck Cancer SPORE: Overcoming Treatment Resistance in Head and Neck Cancer

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SUMMARY Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer globally. Current treatments are morbid, even for patients who are cured, and there are over 13,000 deaths in the US from HNSCC annually. HPV-negative HNSCC is commonly resistant to DNA damaging therapy, EGFR inhibition and immunotherapy. HPV-associated tumors are highly treatment-responsive, but 20-30 percent recur. Even with immune checkpoint inhibition, the majority of these patients succumb. The Yale Head and Neck SPORE (YHN- SPORE) represents highly translational researchers with deep disease-based expertise who leverage the extraordinary scientific strength at Yale Cancer Center, to improve treatment for patients with this terrible malignancy. YHN-SPORE investigators have significantly impacted the field of HNSCC through training, and translational and clinical research. Basic scientists bring rigorous methodology to bear. The YHN-SPORE seeks to address critical barriers to cure of HNSCC due to resistance to immune, DNA damaging and targeted therapy through these specific aims: Aim 1: To overcome resistance to EGFR inhibition in HNSCC by targeting active conformations of ErbB family members; Aim 2: To advance rational synthetic lethal combination therapy to the clinic in HPV-negative HNSCC; Aim 3: To advance combination demethylating therapy with immune checkpoint inhibition to the clinic for HPV-mediated HNSCC, with mechanistic studies and characterization of immune response; Aim 4: To bolster the foundation for HNSCC research through our Administrative, Biospecimen and Biostatistics/Bioinformatics cores, to engage institutional resources and the wider SPORE community; and Aim 5: To advance new research and to foster the next generation of HNSCC translational researchers through a Developmental Research Program, a Career Enhancement Program, and interaction and collaboration with the wider SPORE and HNSCC research communities. The overarching theme of the 3 coordinated projects is overcoming treatment resistance, spanning mechanistic insights into resistance to current treatment modalities and immunotherapy; translational validation; human endpoints to underpin future trials of novel strategies to circumvent resistance; mechanistic confirmation in correlative studies; and clinical trials in HPV-negative and HPV-driven HNSCC. Anticipated translational outcomes of the YHN-SPORE are: (1) conformationally sensitive inhibitors to overcome resistance to EGFR inhibition in HNSCC; (2) clinical safety and pharmacodynamic data combined aurora A kinase/WEE1 inhibition in HPV-negative HNSCC; (3) proof-of- concept and immunoprofiling data to support development of combined demethylation and immunotherapy in HPV-mediated HNSCC; (4) novel models and genomically-characterized tumors to enable HNSCC translational research; and (5) a diverse group of young investigators who will emerge as the generation who cure HNSCC.