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

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.

Grant Number: 3P50DE030707-05S1
NIH Institute/Center: NIH
Principal Investigator: BARBARA BURTNESS