Abstract 5243: STAT3 inhibition as chemoprevention in a chemically induced mouse model of HNSCC
Authors: Peyser Noah D. , Wang Lin , Acquafondata Marie , Freilino Maria , Li Hua , Zeng Yan , Sen Malabika , Gooding William E. , Johnson Daniel E. , Grandis Jennifer R. 
Published: July 2016

Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is frequently fatal due to carcinogen-induced field cancerization, leading to second primary tumor formation in ∼4% of patients per year. Effective chemoprevention could improve survival. Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor and rational therapeutic target in HNSCC. We recently reported that loss of function of PTPRT (protein tyrosine phosphatase receptor type T), a direct STAT3 phosphatase, by frequent somatic mutation or promoter methylation leads to hyper-phosphorylation of STAT3 and may predict sensitivity to STAT3 inhibition using Stattic. In the present study, we sought to evaluate the contribution of PTPRT to chemical carcinogenesis and sensitivity to Stattic-mediated HNSCC chemoprevention in the 4-NQO (4-nitroquinoline 1-oxide) model in vivo using PTPRT wild-type (WT) or knockout (KO) mice.
Methods: PTPRT WT or KO mice received 4-NQO-containing water (100 μg/mL) for 12 weeks. At experiment initiation, a subset of mice received vehicle (PBS) or 50 mg/kg Stattic by oral gavage Q5D. After 12 weeks of 4-NQO administration, mice were randomized to receive vehicle/Stattic for 12 additional weeks. Mice were then sacrificed followed by tongue excision for H&E and IHC analysis. Histologic assessment of dysplasia was scored from 0 to 6 (normal to invasive SCC).
Results: By week 3, we observed unexpected combined toxicity of 4-NQO and Stattic, with 3 mouse deaths. Combined treatment was suspended until the end of the 12-week 4-NQO administration period, and no further toxicity was noted. At the end of the 24-week experiment, we observed a diverse range of neoplasias in the control group, with 7/13 (53.8%) exhibiting SCC of which 4 (30.8%) were invasive. Using a rank transformation statistic, we detected no significant effect of PTPRT status (P = 0.9985) or interaction between PTPRT status and treatment (P = 1.0) with respect to pathology scores. Further analysis revealed a trend toward effective Stattic-mediated chemoprevention (P = 0.0831). Interestingly, the only two mice with normal-appearing oral epithelia were both PTPRT KO and treated with Stattic.
Conclusions: PTPRT status does not appear to predict susceptibility to 4-NQO-mediated carcinogenesis, nor sensitivity to Stattic-mediated chemoprevention in this mouse model of HNSCC initiation. Nevertheless, we observed a trend toward effective chemoprevention in Stattic-treated mice supporting a role for STAT3 in HNSCC carcinogenesis.
Citation Format: Noah D. Peyser, Lin Wang, Marie Acquafondata, Maria Freilino, Hua Li, Yan Zeng, Malabika Sen, William E. Gooding, Daniel E. Johnson, Jennifer R. Grandis. STAT3 inhibition as chemoprevention in a chemically induced mouse model of HNSCC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5243.