Abstract 1766: Growth modulation of head and neck cancer via Sgk-1 inhibition: a novel modality of local control
Authors: Berdel Henrik O. , Yin Hongyu , Liu Jun , Middleton Chris , Yanasak Nathan , Abdelsayed Rafik , Berdel Wolfgang E. , Mozaffari Mahmood , Yu Jack C. , Baban Babak 
Published: May 2015

Introduction: Squamous cell carcinoma (SCC) of the skin is frequently aggressive in its biologic behavior, and the prognosis with metastatic disease is dismal. Nevertheless it is highly curable if detected early, usually via surgical excision. Large and repeat excision can cause considerable functional and cosmetic deformity, and in advanced stages may not be desirable. Serum glucocorticoid-regulated kinase-1 (SGK-1) is a serine-threonine kinase that has recently been found to activate β-catenin, part of intracellular components of the Wnt-signaling pathway. β-catenin has been implicated in promoting the stem cell compartment, as well as tumor growth. SGK-1 has been shown to inactivate glycogen synthase kinase-3β (GSK-3β). Importantly, GSK-3β deactivates β-catenin while also serving as a pivotal regulator of the mitochondrial permeability transition pore and cell fate determinant. In this study we tested the effects of local SGK-1 inhibition on tumor growth, as well as expression of CD44 and human epidermal growth factor receptor 2 (HER-2). CD44 is recognized as a key cell surface marker for stem cells in human head and neck cancer, while HER-2 is a trans-membrane protein linked to its migration and invasion. Methods: A human SCC cell line (HTB41) was established in vitro. Athymic mice (n=12) were then injected with HTB41(2x106 cells/animal), and tumor growth monitored. At 6mm, tumors were injected with an SGK-1 Inhibitor (Group 1) twice weekly (20 mg/mouse per injection). Controls (Group 2) received vehicle only (PBS), Group 3 weekly intraperitoneal Cisplatin (5mg/kg), and Group 4 both Cisplatin and SGK-1 inhibitor. Once the first tumor reached 12mm in size, the mice were sacrificed and tumor cells subjected to flow-cytometry, and statistical analysis. 2-tailed t-tests were performed, and p-values &lt;0.05 considered significant. Results: The local inhibition of SGK-1 in combination with Cisplatin showed a significantly slower growth than the control group (p = 0.015). The growth rates were 1.80 +/- 0.12, 2.27 +/- 0.51, 0.89 +/- 0.87, 0.68 +/- 0.40 mm2/day (mean +/- sd) for Groups 1 to 4 respectively. Furthermore, Group 1 showed a right shift compared to controls. At 3%, CD44 expression was highest in Group 2 versus 1%, 0.2 % and 0.07% in Groups 1, 3, and 4. HER-2+ cells were 1% in Group 2, and 0.2%, 0.1% and 0.02% in Groups 1, 3 and 4. Conclusions: Decreased expression of CD44 in Group 4 suggests depletion of tumor stem cells, and may imply less metastatic potential. In addition, lower HER-2 expression in Group 4 may indicate less malignant behavior and perhaps better survival. It should be noted that other pathways might have quickly bypassed a preliminary growth suppressing effect of SGK-1 inhibition alone. Finally, SGK-1 inhibition via local injection added to systemic Cisplatin increases tumor growth suppression, and represents a potential modality of local control for palliation in advanced cases.

Citation Format: Henrik O. Berdel, Hongyu Yin, Jun Liu, Chris Middleton, Nathan Yanasak, Rafik Abdelsayed, Wolfgang E. Berdel, Mahmood Mozaffari, Jack C. Yu, Babak Baban. Growth modulation of head and neck cancer via Sgk-1 inhibition: a novel modality of local control. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1766. doi:10.1158/1538-7445.AM2014-1766