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.
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.
|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|
|Li, Hua; Wawrose, John S; Gooding, William E et al. (2014) Genomic analysis of head and neck squamous cell carcinoma cell lines and human tumors: a rational approach to preclinical model selection. Mol Cancer Res 12:571-82|
|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|
|Sen, Malabika; Paul, Kathleen; Freilino, Maria L et al. (2014) Systemic administration of a cyclic signal transducer and activator of transcription 3 (STAT3) decoy oligonucleotide inhibits tumor growth without inducing toxicological effects. Mol Med 20:46-56|
|Stabile, Laura P; He, Guoqing; Lui, Vivian Wai Yan et al. (2013) c-Src activation mediates erlotinib resistance in head and neck cancer by stimulating c-Met. Clin Cancer Res 19:380-92|
|Wheeler, Sarah; Siwak, Doris R; Chai, Raymond et al. (2012) Tumor epidermal growth factor receptor and EGFR PY1068 are independent prognostic indicators for head and neck squamous cell carcinoma. Clin Cancer Res 18:2278-89|
|Egloff, Ann Marie; Grandis, Jennifer R (2011) Response to combined molecular targeting: defining the role of P-STAT3. Clin Cancer Res 17:393-5|
|Sahu, Nivedita; Grandis, Jennifer Rubin (2011) New advances in molecular approaches to head and neck squamous cell carcinoma. Anticancer Drugs 22:656-64|
|Leeman-Neill, Rebecca J; Seethala, Raja R; Singh, Shivendra V et al. (2011) Inhibition of EGFR-STAT3 signaling with erlotinib prevents carcinogenesis in a chemically-induced mouse model of oral squamous cell carcinoma. Cancer Prev Res (Phila) 4:230-7|
Showing the most recent 10 out of 43 publications