HPV/p16-positive head and neck squamous cell carcinoma (HNSCC) patients have higher overall survival (OS) rates than do HPV/p16-negative patients. The primary treatment of this cancer is radiotherapy (RT) either alone or in combination with chemotherapy and HPV positivity is known to render tumors more sensitive to RT. However, to date, the underlying mechanisms of this favorable phenomenon remain unknown. The proposed study is aimed at addressing this important question via in vitro studies of molecular mechanisms, in vivo tests of tumor response, and analyses of human tumor tissue. Our long-term objective is to identify the mechanisms that govern favorable prognosis in HPV/p16-positive OPSCC and use this information to improve treatment outcomes for all patients. To fulfill this goal, we have generated preliminary data identifying a novel mediator of radioresistance, TRIP12, which is inhibited by p16 expression leading to enhanced response to radiotherapy. The immediate goals of this application are reflected by three specific aims: i) establish the regulatory connection between p16 and TRIP12 and determine the role of TRIP12 in radiation sensitivity, ii) examine the downstream effects of TRIP12 signaling on radioresponse, and iii) verify that TRIP12 expression is a prognostic marker in HNSCC as well as a predictive marker for radiosensitizers that target this signaling pathway. We hope that by delineating the novel p16-TRIP12 signaling network we can provide valuable insight into the phenomenon of radioresistance as well as develop rationally targeted radiosensitizers for clinical use.

Public Health Relevance

HPV/p16-positive head and neck squamous cell carcinoma (HNSCC) patients have higher overall survival (OS) rates than do HPV/p16-negative patients but how HPV/p16 influences treatment outcomes is unknown. We have found a novel pathway from p16 to TRIP12 that partially regulates response to radiation in these tumors and that TRIP12 expression is associated with poor outcome in HNSCC. Our long-term objective is to identify the mechanisms that govern favorable prognosis in HPV/p16 positive, TRIP12 negative HNSCC and use this information to improve treatment outcomes in patients with HPV/p16-negative TRIP12 positive disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168485-10
Application #
10101631
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Buchsbaum, Jeffrey
Project Start
2019-03-01
Project End
2022-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
10
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Wang, L; Zhang, P; Molkentine, D P et al. (2017) TRIP12 as a mediator of human papillomavirus/p16-related radiation enhancement effects. Oncogene 36:820-828
Skinner, Heath D; Giri, Uma; Yang, Liang et al. (2016) Proteomic Profiling Identifies PTK2/FAK as a Driver of Radioresistance in HPV-negative Head and Neck Cancer. Clin Cancer Res 22:4643-50
Meyn, Raymond E; Krishnan, Sunil; Skinner, Heath D (2016) Everything Old Is New Again: Using Nelfinavir to Radiosensitize Rectal Cancer. Clin Cancer Res 22:1834-6
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