TP53 is the most commonly somatically mutated gene in all cancers, and is altered in as many as 85% of squamous cell carcinoma of the oral tongue (SCCOT) cases. While some TP53 mutations lead to a loss of wild-type p53 function, many TP53 mutations have been identified to confer gain of functions (GOF) that promote invasion, metastasis, genomic instability, and cancer cell proliferation. However, the determination of whether a specific mutation will lead to GOF, and the mechanisms involved in mutant p53 GOF activity remain elusive. Our long-term goal is to understand the role of TP53 mutations in promoting aggressiveness of SCCOT, and based on this information, to design and develop effective and precise cancer therapies for SCCOT patients. The objective of this proposal is to understand the impact of different TP53 mutations on the clinical outcomes of SCCOT patients, and to further investigate the mechanisms involved in mutant p53 GOF activity that promote tumor progression and metastasis. Our central hypothesis is that high-risk p53 mutations identified by our newly-developed EAp53 scoring system are associated with mutant p53 GOF activity that contributes to disease progression, metastasis and adverse clinical outcomes, and that mutant p53s achieve gain oncogenic function through positive regulation of the oncogenic transcription factor, FoxM1's expression and stimulation of focal adhesion kinase (FAK) through inhibition of AMPK-mediated signaling in both transcription-dependent and -independent manners. This hypothesis has been formulated on the basis of our recent exciting preliminary data. The rationale for the proposed study is that successful completion of proposed studies will establish clinical significance of EAp53 stratification in predicting clinic outcomes or SCCOT patients, and will provide mechanistic insights into GOF of p53 mutations. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Aim 1: Demonstrate the ability of EAp53 to identify p53 mutations associated with adverse clinical outcomes for HNSCC patients, and correlate high-risk p53 mutations with both in vitro and in vivo mutant p53 gain-of-function activity; 2) Aim 2: Demonstrate that high-risk mutant p53 GOF activity inhibits AMPK signaling leading to invasive tumor cell growth and metastasis through transcription-dependent and transcription-independent mechanisms, and 3) Aim 3: Demonstrate that the TP53 codon 72 polymorphism modulates the GOF activity of mutant p53-mediated AMPK inhibition and promotes tumor invasive cell growth and metastasis. Our proposed study is innovative given that the proposed mechanisms and the approaches for studying GOF mutp53 have not been reported before. Our proposed study is also significant since it not only enhances our understanding of the role of mutant p53 in mediating SCCOT disease progression, but also enables us to better prognosticate and treat HNSCC patients at high risk for disease progression and recurrence based on TP53 mutational status.

Public Health Relevance

In the prior funding period, we found that TP53 is the most commonly mutated gene in tongue cancer. In the studies proposed here, we will further develop a method called EAp53 that is used to identify p53 mutations which make oral cancer cells more aggressive. We expect that completion of this project will help us to better identify patients with more aggressive tongue cancers and help us to find better ways to treat this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014613-14
Application #
9402598
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Wang, Chiayeng
Project Start
2002-04-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Surgery
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Wang, Jin; Xie, Tongxin; Wang, Bingbing et al. (2017) PD-1 Blockade Prevents the Development and Progression of Carcinogen-Induced Oral Premalignant Lesions. Cancer Prev Res (Phila) 10:684-693
Tanaka, Noriaki; Zhao, Mei; Tang, Lin et al. (2017) Gain-of-function mutant p53 promotes the oncogenic potential of head and neck squamous cell carcinoma cells by targeting the transcription factors FOXO3a and FOXM1. Oncogene :
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
Zhou, Ge; Liu, Zhiyi; Myers, Jeffrey N (2016) TP53 Mutations in Head and Neck Squamous Cell Carcinoma and Their Impact on Disease Progression and Treatment Response. J Cell Biochem 117:2682-2692
Osman, Abdullah A; Monroe, Marcus M; Ortega Alves, Marcus V et al. (2015) Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence. Mol Cancer Ther 14:608-19
Neskey, David M; Osman, Abdullah A; Ow, Thomas J et al. (2015) Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer. Cancer Res 75:1527-36
Fitzgerald, A L; Osman, A A; Xie, T-X et al. (2015) Reactive oxygen species and p21Waf1/Cip1 are both essential for p53-mediated senescence of head and neck cancer cells. Cell Death Dis 6:e1678
Osman, Abdullah A; Neskey, David M; Katsonis, Panagiotis et al. (2015) Evolutionary Action Score of TP53 Coding Variants Is Predictive of Platinum Response in Head and Neck Cancer Patients. Cancer Res 75:1205-15
Zhou, Ge; Wang, Jiping; Zhao, Mei et al. (2014) Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation. Mol Cell 54:960-74
Xie, Tong-Xin; Zhou, Ge; Zhao, Mei et al. (2013) Serine substitution of proline at codon 151 of TP53 confers gain of function activity leading to anoikis resistance and tumor progression of head and neck cancer cells. Laryngoscope 123:1416-23

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