Head and neck squamous cell carcinoma (HNSCC) is the seventh leading cause of cancer-related deaths globally, killing more than 375,000 individuals yearly. Cancers arise because of DNA alterations (i.e. mutations) activating genes that act like gas pedals (oncogenes) and destroying the function of other genes that act like cellular brakes (tumor suppressors). For HNSCC, most of the cancer-causing mutations are in tumor suppressor genes that are very difficult to target with drugs. Unlike some other cancers, there are no good therapies to specifically target alterations in HNSCC in a personalized manner. NOTCH1 is a tumor suppressor gene frequently mutated in HNSCC. We recently discovered tha...

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Head and neck squamous cell carcinoma (HNSCC) is the seventh leading cause of cancer-related deaths globally, killing more than 375,000 individuals yearly. Cancers arise because of DNA alterations (i.e. mutations) activating genes that act like gas pedals (oncogenes) and destroying the function of other genes that act like cellular brakes (tumor suppressors). For HNSCC, most of the cancer-causing mutations are in tumor suppressor genes that are very difficult to target with drugs. Unlike some other cancers, there are no good therapies to specifically target alterations in HNSCC in a personalized manner. NOTCH1 is a tumor suppressor gene frequently mutated in HNSCC. We recently discovered that HNSCC tumors with NOTCH1 mutations die when treated with drugs that inhibit a cellular enzyme known as PI3K. Fortunately, several drugs to inhibit PI3K exist and we have shown in the laboratory that these drugs kill HNSCC tumors with NOTCH1 mutations. In this project, we propose experiments to understand the dependency of NOTCH1-mutant HNSCC on the PI3K pathway, and models to optimize targeting this pathway in NOTCH1-mutant HNSCC to overcome mechanisms of drug resistance. In addition, we will leverage human clinical specimens from an ongoing clinical trial of a PI3K inhibitor in HNSCC to confirm molecular markers predictive of drug response. Our proposed research will have positive impact because it will be the first to establish a treatment specific for NOTCH1-mutant HNSCC to any class of drugs and may inform the development of the first personalized therapy for HNSCC. Also, we may define an unknown mechanism of regulation of a molecule in the PI3K pathway – PDK1 - and identify clinically relevant targets that enhance the effectiveness and durability of PI3K inhibition in NOTCH1-mutant HNSCC. Because NOTCH1 mutations are common in other squamous cell carcinomas, including those of skin, esophagus, and lung, our findings will likely have implications beyond HNSCC.

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