Synthetic Lethal Therapy for HPV-Negative Head and Neck Cancer

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Project Abstract / Summary Head and neck squamous cell carcinomas (HNSCC) affect more than 890,000 individuals annually worldwide, and lead to over 450,000 deaths. Although significant progress has been made treating HNSCC including immune checkpoint blockade (ICB), intrinsic and adaptive resistance present great challenges to improving patient outcomes. In these cancers, the most dominant genetic alteration is mutation of the tumor suppressor TP53, which accounts for over 85% of patients. The Yale Head and Neck SPORE seeks to address critical barriers to cure of HNSCC due to resistance to immune, DNA damaging and targeted therapy. Our previous work identified synthetic lethality of inhibition of Aurora Kinase A (AURKA) and WEE1, a G2/M checkpoint kinase, leading to induction of cell death for HNSCC cell lines in vitro and xenografts and patient-derived xenografts in vivo. These innovative combinations of kinase inhibitors represent a completely new approach to treating TP53- mutated cancer. This study will help us to combination therapies to the clinic of HPV-negative HNSCC, particularly in the context of synthetic lethality and TP53mut-mediated drug response targeting cell cycle regulators. The proposed work will determine how different TP53 mutations affect drug response to AURKA inhibitor in combination with WEE1 inhibitor in HNSCC. Aim 1 will explore the relationship between TP53 mutation genotype and drug response to AURKA and WEE1 inhibitors in HPV-negative HNSCC cells. We will perform treatment combinations on isogenic cell lines with different TP53 genotypes including mutations strongly disruptive, weakly disruption, gain of function, loss of function and wild type. Aim 2 will preclinically assess the efficacy of the combinational treatment to generate response biomarkers and model potential trial design by using a new genetically engineered mouse model of HNSCC driven both by Tp53 and Cdkn2a mutations. This Diversity Supplement will provide Mr. Barrantes with an opportunity to learn and develop technical, communicative, and critical thinking research skills in the realm of cancer therapeutics. This supplement will also support additional pre-requisite coursework, and the opportunity for him to demonstrate his ability to complete graduate level coursework in the Yale Cancer Biology T32 Introduction to Cancer Biology Course. We expect his research success to include at least one scientific publication resulting from this project. Altogether, we anticipate that this research experience will provide Mr. Barrantes with opportunities for development as a productive researcher and more competitive application for medical or graduate school.