Abstract
Abstract Background: Recurrent/metastatic head and neck squamous cell carcinoma (SCCHN) and salivary gland malignancies are difficult to treat with limited standard of care options at the present time. Glycogen Synthase Kinase-3beta (GSK-3beta), a serine/threonine protein kinase, has been implicated as a potential therapeutic target in human cancer. Our in vivo studies demonstrated that our novel GSK-3 inhibitors significantly potentiated the effects of conventional chemotherapy in patient-derived xenograft models of glioblastoma and breast cancer leading to regression of tumors. In order to develop a rationale to test our novel GSK-3 inhibitors in head and neck (H&N) malignancies, we evaluated the expression pattern of GSK-3beta in human H&N benign tissue and malignant tumors. Methods: We used immunohistochemical staining of H&N tumor tissue Microarray (TMA), 48 total cases (20 benign tissues, 28 malignant), to study the expression pattern of GSK-3beta. GSK-3beta nuclear accumulation was defined as positive staining of more than 50% of cancer cell nuclei throughout the tumor regardless of cytoplasmic staining. Results: Of the 20 malignant H&N samples (15 SCCHN, 1 nasopharyngeal and 5 other histology), 13 (65%) were found to have aberrant nuclear accumulation of GSK-3beta. Amongst SCCHN, 73% (11 of 15 samples) had aberrant nuclear accumulation of GSK-3beta. In contrast, none (0%) of the 11 benign non-salivary H&N tissue showed detectable expression of GSK-3beta. Of interest, 60% of salivary adenoid cystic carcinoma specimens and 44% of benign salivary gland tissue showed GSK-3beta expression. Conclusions: Our results demonstrate for the first time, that there is aberrant nuclear expression of GSK-3beta in SCCHN. This finding supports further exploring of our novel GSK-3beta inhibitor as a potential therapeutic target for recurrent/metastatic SCCHN and also, as a potential prognostic and predictive biomarker for risk of recurrent disease and chemo- or radio-resistance. Its role in salivary gland malignancies requires further studying. Citation Format: Maria Matsangou, Andrey Ugolkov, Timothy J. Taxter, Sandeep Samant, Andrew P. Mazar, Francis J. Giles. Aberrant nuclear expression of GSK-3beta in human head and neck carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1127. doi:10.1158/1538-7445.AM2017-1127
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