Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168485-09
Application #
9657651
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Buchsbaum, Jeffrey
Project Start
2019-03-01
Project End
2022-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260

  Publications

Clump, David A; Pickering, Curtis R; Skinner, Heath D (2018) Predicting Outcome in Head and Neck Cancer: miRNAs with potentially big effects. Clin Cancer Res :
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 P et al. (2017) Integrative Analysis Identifies a Novel AXL-PI3 Kinase-PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer. Clin Cancer Res 23:2713-2722
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
Bridges, Kathleen A; Chen, Xingxing; Liu, Huifeng et al. (2016) MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Oncotarget 7:71660-71672
Raju, Uma; Molkentine, David P; Valdecanas, David R et al. (2015) Inhibition of EGFR or IGF-1R signaling enhances radiation response in head and neck cancer models but concurrent inhibition has no added benefit. Cancer Med 4:65-74
Ang, K Kian; Zhang, Qiang; Rosenthal, David I et al. (2014) Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 32:2940-50
Bridges, Kathleen A; Toniatti, Carlo; Buser, Carolyn A et al. (2014) Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells. Oncotarget 5:5076-86
Wilson-Edell, Kathleen A; Kehasse, Amanuel; Scott, Gary K et al. (2014) RPL24: a potential therapeutic target whose depletion or acetylation inhibits polysome assembly and cancer cell growth. Oncotarget 5:5165-76

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