The results of this proposal are likely to develop knowledge for improving the standard of care for treatment of head and neck squamous cell cancer (HNSCC). Of all cancers reported in the US 3-5 % are HNSCCs. Survival rates for this cancer are poor. Only about 50% of patients will survive over the 5-year period following diagnosis. Human papillomavirus (HPV) causes a subset of HNSCCs. HPV-positive (HPV+) HNSCC incidence has nearly tripled in the last 30 years. While these HPV+ HNSCCs benefit from improved survival compared to their HPV- negative (HPV-) counterparts, their increased incidence makes understanding this disease a priority. HPV- cancers suffer much worse survival, yet neither therapies nor survival have changed dramatically over the past few decades. Furthermore, both HPV+ and HPV- HNSCC patients suffer severe co-morbidities associated with current therapies; making the development of new therapies with less toxicity and tissue damage highly desirable. We have shown that an immune response is required for long-term cures of HPV+ HNSCC following standard of care cisplatin/radiation therapy (CRT). Our findings and those of others also show that tumor metabolism, and its consequent production of high lactate in the tumor microenvironment, attenuates this immune response. We recently showed that targeting HPV oncogene related changes in the metabolism-regulating mTOR pathway enhances immune-mediated tumor clearance and long-term survival in vivo, while also synergizing with CRT to enhance direct cell cytotoxicity (Coppock et al. (2013) Neoplasia 5:620-30.). Our preliminary data demonstrate that the latter may also be applicable to HPV- HNSCCs, also commonly activated in mTOR signaling. We will follow up on these important observations by: 1) further defining the mechanism by which the HPV-16 E6 oncoprotein activates metabolism by promoting the mTOR pathway 2) determining how inhibition of mTOR signaling enhances CRT-induced cytotoxicity and the CRT-initiated immune response and 3) Determining whether systemic mTOR blockade affects the immune compartment by enhancing T lymphocyte memory cell differentiation to improve therapeutic efficacy. Potential impact: We expect that these studies will impact patient care by delineating the pathophysiology of mTOR activation in both the tumor and immune compartments of HPV+ HNSSC. The data will provide the foundation for intervening in the biology of either or both compartments. We will determine the optimal timing of an mTOR blockade that leads to the greatest improvement CRT-induced tumor clearance and overall survival rates by decreasing recurrence and metastasis. Importantly, the findings of this project could be rapidly translated into clinical trials of the appropriate disease state via the use of mTOR inhibitors currently in development.

Public Health Relevance

Human papillomavirus (HPV), a virus that infects and induces changes in normal oral cells, is the most identifiable cause of head and neck squamous cell cancer (HNSCC). Our findings indicate that targeting of cancerous, HPV-related changes to a specific cellular metabolism regulating signaling pathway with certain drugs may improve current standard of care therapy for HPV-positive HNSCC, and that the studied treatment regimen may also benefit HPV-negative cancers. Cultured cancer cells and pre-clinical mouse models of head and neck cancer will be used in order to gain information that will provide a basis for using these treatment combinations in cancer patients for improved long-term survival.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Sanford Research/Usd
Sioux Falls
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Anderson, Ruthellen H; Lensing, Cody J; Forred, Benjamin J et al. (2018) Differentiating Antiproliferative and Chemopreventive Modes of Activity for Electron-Deficient Aryl Isothiocyanates against Human MCF-7 Cells. ChemMedChem 13:1695-1710
Johnson, Tyler B; Mechels, Keegan; Anderson, Ruth Ellen et al. (2018) Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of FOXP1. Sci Rep 8:16161
Butler, Merlin G; Hossain, Waheeda A; Tessman, Robert et al. (2018) Preliminary observations of mitochondrial dysfunction in Prader-Willi syndrome. Am J Med Genet A 176:2587-2594
Sane, Sanam; Hafner, Andre; Srinivasan, Rekha et al. (2018) UBXN2A enhances CHIP-mediated proteasomal degradation of oncoprotein mortalin-2 in cancer cells. Mol Oncol 12:1753-1777
Anderson, Ruthellen H; Kerkvliet, Jason G; Otta, Jaelin J et al. (2018) Generation of a CLTA reporter human induced pluripotent stem cell line, CRMi001-A-1, using the CRISPR/Cas9 system to monitor endogenous clathrin trafficking. Stem Cell Res 33:95-99
Lucido, Christopher T; Callejas-Valera, Juan L; Colbert, Paul L et al. (2018) ?2-Adrenergic receptor modulates mitochondrial metabolism and disease progression in recurrent/metastatic HPV(+) HNSCC. Oncogenesis 7:81
Miszuk, Jacob M; Xu, Tao; Yao, Qingqing et al. (2018) Functionalization of PCL-3D Electrospun Nanofibrous Scaffolds for Improved BMP2-Induced Bone Formation. Appl Mater Today 10:194-202
Anderson, Ruthellen H; Francis, Kevin R (2018) Modeling rare diseases with induced pluripotent stem cell technology. Mol Cell Probes 40:52-59
Amatya, Christina; Radichev, Ilian A; Ellefson, Jacob et al. (2018) Self-Transducible Bimodal PDX1-FOXP3 Protein Lifts Insulin Secretion and Curbs Autoimmunity, Boosting Tregs in Type 1 Diabetic Mice. Mol Ther 26:184-198
Yao, Qingqing; Liu, Yangxi; Selvaratnam, Balaranjan et al. (2018) Mesoporous silicate nanoparticles/3D nanofibrous scaffold-mediated dual-drug delivery for bone tissue engineering. J Control Release 279:69-78

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