Dr. Neskey's short-term goals are to obtain outstanding research training in methodological, conceptual and theoretical approaches to laboratory-based scientific investigation which will help him determine the role of non-muscle Myosin IIA (NMIIA) in regulating p53 as a tumor suppressor in head and neck cancer. The K08 Award will enable him to further mature as a scientist, and develop the skillset, tools, knowledge, and expertise to excel in the scientific arena. It is anticipated that during the K08 funding period he will be well positioned to submit a Research Project Grant (R01) application, representing the natural progression of his research activities from this K08 grant proposal. Dr. Neskey's long-term career objective is to spearhead an independently funded, comprehensive research program as a surgeon-scientist exploring the mechanisms of tumor cell invasion and metastasis that complements and enhances his clinical practice focused on the care of head and neck cancer patients. Ultimately, discoveries from his laboratory will be translated to the clinical realm with the goal of improving outcomes of patients suffering from oral cancer. In order to achieve his career goals, Dr. Neskey has partnered with Drs. Rosenzweig, Watson, and Garrett- Mayer for scientific mentorship. Each committee member has an established record as a mentor and an independent investigator. In addition to the strong mentoring committee, the Departments of Otolaryngology and Pharmacology at the Medical University of South Carolina along with Hollings Cancer Center have provided protected time, laboratory space, and a significant start up package the ensure a solid and productive research environment. Dr. Neskey has also developed an external advisory committee comprised of two of previous mentors, Drs. Jeffrey Myers and Cynthia Morton who provide additional expertise in the fields of p53 biology and tumor genetics respectively which will complement his MUSC based mentoring committee. Head and neck cancer accounts for over 60,000 new cancer diagnoses annually in the U.S. with 25-30% of patients ultimately dying from their disease, which suggests a significant need for continued research to identify factors contributing to poor outcomes in these patients. A promising area of research is high-risk mutations in the tumor suppressor gene, TP53, which are associated with decreased survival and are harbored in approximately 50% of these cancers. To date, it is not currently understood how these mutations make head and neck tumor cells more invasive. The studies described in this proposal will directly address the role of non- muscle Myosin IIA in the tumor suppressor capability of mutant TP53 in head and neck cancer and demonstrate NMIIA dysfunction results in characteristics of high-risk mutant p53 including increased cell invasion and tumor formation. Ultimately, this research could lead to precise therapies targeting these aggressive tumors and subsequently improving the survival of patients with head and neck cancer.
The relevance of this project to public health is nearly 60,000 patients will develop squamous cell carcinoma of the head and neck in United States in 2015 of which half will die of their disease which suggests there is a significant need for continued research to identify factors contributing to poor outcomes in head and neck cancer patients. One promising area is approximately 50% of these cancers harbor high-risk mutations in the tumor suppressor gene, TP53, which are associated with aggressive disease and decreased survival but it is not currently understood how these mutations make head and neck tumor cells more invasive. The studies described in this proposal will validate the role of a key protein, non-muscle Myosin IIA, in the increased invasiveness of head and neck cancers harboring high-risk TP53 mutations, which ultimately could lead to precise therapies targeting these aggressive tumors and subsequently improving the survival of patients with head and neck cancer.
| Grauzam, Stéphane; Brock, Amanda M; Holmes, Casey O et al. (2018) NEDD9 stimulated MMP9 secretion is required for invadopodia formation in oral squamous cell carcinoma. Oncotarget 9:25503-25516 |
| Coaxum, Sonya D; Tiedeken, Jessica; Garrett-Mayer, Elizabeth et al. (2017) The tumor suppressor capability of p53 is dependent on non-muscle myosin IIA function in head and neck cancer. Oncotarget 8:22991-23007 |
