Human papillomavirus (HPV) associated head and neck cancer is a growing public health concern. These patients commonly present at a younger age and with more advanced stage disease than patients with traditional tobacco and alcohol associated head and neck squamous cell carcinoma (HNSCC). Paradoxically, these HPV-associated tumors show notably improved survival outcomes. Mechanisms underlying these improved outcomes remain unclear. The work proposed in this Pathways to Independence Award has two primary goals: 1) to facilitate career development of the principal investigator (PI) and to help establish his independence to lead a research program investigating radiation response in virally associated cancers;and, 2) to understand how HPV-associated HNSCC differs from traditional HNSCC in response to radiation and chemotherapy. During the mentored phase of research, the PI will obtain additional training in molecular virology, human papillomavirus biology, and mouse models of cancer. The research conducted during the mentored phase will examine why HPV-associated HNSCC are more sensitive than traditional HNSCC to radiation and chemotherapy and to examine the ability of epidermal growth factor receptor (EGFR) inhibitors to sensitize HPV-associated head and neck cancer to radiation despite low levels of EGFR expression. During the independent phase, research will examine the impact of HPV viral proteins on EGFR inhibitor-mediated radiosensitization and the impact of EGFR loss on radiosensitization strategies. These studies will provide new clues regarding mechanisms of increased sensitivity to radiation and chemotherapy and may identify important new targets for therapy development to further improve outcome for patients with both HPV-associated and non-HPV-associated head and neck cancer.
Head and neck squamous cell carcinomas associated with human papillomavirus (HPV) infection are rapidly increasing in global incidence, often present at an advanced stage, are commonly treated with radiation and chemotherapy, and generally show an improved prognosis;nevertheless, selection of optimal therapy remains ill defined. This proposal investigates molecular mechanisms of treatment response with a goal to identify novel means of radiosensitization, the relationship between epidermal growth factor receptor (EGFR) signaling and radiosensitivity, and potential novel mechanisms of radiosensitization. The ultimate objective is to design rationale combinations of radiation and chemotherapy to further improve outcome and/or decrease treatment toxicity.
|Rosenberg, Stephen A; Francis, David M; Hullet, Craig R et al. (2016) Online patient information from radiation oncology departments is too complex for the general population. Pract Radiat Oncol :|
|Morris, Zachary S; Weichert, Jamey P; Saker, Jarob et al. (2015) Therapeutic combination of radiolabeled CLR1404 with external beam radiation in head and neck cancer model systems. Radiother Oncol 116:504-9|
|Stein, Andrew P; Saha, Sandeep; Kraninger, Jennifer L et al. (2015) Prevalence of Human Papillomavirus in Oropharyngeal Cancer: A Systematic Review. Cancer J 21:138-46|
|Brand, Toni M; Iida, Mari; Stein, Andrew P et al. (2015) AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma. Clin Cancer Res 21:2601-12|
|Kimple, Randall J; Harari, Paul M; Torres, Alexandra D et al. (2013) Development and characterization of HPV-positive and HPV-negative head and neck squamous cell carcinoma tumorgrafts. Clin Cancer Res 19:855-64|
|Kimple, Randall J; Smith, Molly A; Blitzer, Grace C et al. (2013) Enhanced radiation sensitivity in HPV-positive head and neck cancer. Cancer Res 73:4791-800|
|Apisarnthanarax, Smith; Swisher-McClure, Samuel; Chiu, Wing K et al. (2013) Applicability of randomized trials in radiation oncology to standard clinical practice. Cancer 119:3092-9|
|Kimple, Adam J; Torres, Alexandra D; Yang, Robert Z et al. (2012) HPV-associated head and neck cancer: molecular and nano-scale markers for prognosis and therapeutic stratification. Sensors (Basel) 12:5159-69|
|Kimple, Randall J; Russo, Suzanne; Monjazeb, Arta et al. (2012) The role of chemoradiation for patients with resectable or potentially resectable pancreatic cancer. Expert Rev Anticancer Ther 12:469-80|