STAT3 is an oncogenic transcription factor that is hyperactivated in many cancers, contributing to growth, survival and therapeutic resistance. The mechanisms mediating increased STAT3 activation in human cancers are incompletely understood. Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer mortality worldwide. We previously reported increased STAT3 activation in HNSCC associated with treatment resistance. Previous reports indicate that protein tyrosine receptor phosphatases T (PTPRT) and D (PTPRD) negatively regulate STAT3 activation. We determined the mutational profile of HNSCC, and detected mutations in the PTPR family in nearly one-third of the cases analyzed. Studies proposed here will test the hypothesis that aberrant STAT3 activation results from PTPR mutations, and that STAT3 is a key therapeutic target in cancers harboring these mutations. We have developed a STAT3-selective decoy that inhibits STAT3 target gene expression in HNSCC tumors treated on a recently completed phase 0 trial. In addition, preliminary evidence indicates that the JAK/STAT inhibitor AZD1480 abrogates STAT3 activation and HNSCC growth. We propose to determine whether tumors that harbor PTPR mutations demonstrate enhanced sensitivity to STAT3 inhibition using relevant preclinical HNSCC models and our unique access to tumors from HNSCC patients enrolled in a presurgical trial of a small molecule JAK/STAT inhibitor.

Public Health Relevance

Signal Transducer and Activator of Transcription 3 (STAT3) is an oncogenic transcription factor that is hyperactivated in a wide variety of cancers, where STAT3 contributes to growth, survival and therapeutic resistance. The mechanisms contributing to increased STAT3 activation in human cancers are incompletely understood. Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer mortality worldwide. We previously reported that STAT3 activation is increased in HNSCC and confers resistance to treatment. Previous studies suggest that protein tyrosine receptor phosphatases T (PTPRT) and D (PTPRD) negatively regulate STAT3 activation. We recently reported the mutational profile of HNSCC, and detected mutations in the PTPR family (including PTPRT, PTPRD) in nearly one third of the cases analyzed. The proposed studies will: 1) determine the contribution of PTPR mutations to STAT3 activation and tumor growth in HNSCC preclinical models;2) elucidate the biological impact of STAT3 inhibitors in HNSCC models harboring PTPR mutations;and 3) determine the in vivo antitumor efficacy of STAT3 inhibition in heterotopic HNSCC tumorgrafts and specimens from HNSCC patients treated on a window-of-opportunity trial with a JAK/STAT inhibitor. Overall, our objective is to identify the subset of HNSCC patients where treatment with a STAT3 targeting agent represents a particularly effective therapeutic strategy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA077308-16A1
Application #
8621469
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Salnikow, Konstantin
Project Start
1998-08-01
Project End
2019-05-31
Budget Start
2014-08-01
Budget End
2015-05-31
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Peyser, Noah D; Pendleton, Kelsey; Gooding, William E et al. (2016) Genomic and Transcriptomic Alterations Associated with STAT3 Activation in Head and Neck Cancer. PLoS One 11:e0166185
Peyser, N D; Freilino, M; Wang, L et al. (2016) Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer. Oncogene 35:1163-9
Peyser, Noah D; Wang, Lin; Zeng, Yan et al. (2016) STAT3 as a Chemoprevention Target in Carcinogen-Induced Head and Neck Squamous Cell Carcinoma. Cancer Prev Res (Phila) 9:657-63
Sen, Malabika; Pollock, Netanya I; Black, John et al. (2015) JAK kinase inhibition abrogates STAT3 activation and head and neck squamous cell carcinoma tumor growth. Neoplasia 17:256-64
Du, Yu; Grandis, Jennifer R (2015) Receptor-type protein tyrosine phosphatases in cancer. Chin J Cancer 34:61-9
Wheeler, Sarah E; Egloff, Ann Marie; Wang, Lin et al. (2015) Challenges in EGFRvIII detection in head and neck squamous cell carcinoma. PLoS One 10:e0117781
Peyser, Noah D; Du, Yu; Li, Hua et al. (2015) Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer. PLoS One 10:e0135750
Pollock, Netanya I; Grandis, Jennifer R (2015) HER2 as a therapeutic target in head and neck squamous cell carcinoma. Clin Cancer Res 21:526-33
Lui, Vivian Wai Yan; Peyser, Noah D; Ng, Patrick Kwok-Shing et al. (2014) Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer. Proc Natl Acad Sci U S A 111:1114-9
Nakajima, Erica C; Laymon, Charles; Oborski, Matthew et al. (2014) Quantifying metabolic heterogeneity in head and neck tumors in real time: 2-DG uptake is highest in hypoxic tumor regions. PLoS One 9:e102452

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