Abstract 3209: Everolimus inhibits angiogenesis and lymphangiogenesis to affect tumor growth in TP53 mutant HNSCC

Abstract Head and neck squamous cell carcinoma (HNSCC) constitutes the eighth most common cancer globally, with the eighth highest mortality rate amongst all cancer types. TP53 is the most frequently mutated gene in HPV -negative HNSCC. HPV-negative HNSCC harboring p53 mutations have the worst clinical outcomes with 50-60% local regional and distant recurrences causing increased morbidity and mortality. TP53 mutations are associated with shorter recurrence-free and overall survival. Angiogenesis and lymphangiogenesis play a causal role in tumor recurrence and lymph node metastasis. Therefore, inhibiting tumor angiogenesis and lymphangiogenesis is important in to preventing tumor recurrence and metastasis of TP53 mutant HNSCC. Previous studies demonstrated that mTOR activates STAT3 to upregulate HIF-1α and its target proteins, VEGF-A and VEGF-C, key molecules involved in angiogenesis and lymphangiogenesis, respectively. Further, mTOR inhibitors suppress autocrine and paracrine growth stimulation of tumor and lymphatic endothelial cells by impairing the VEGF-C/VEGF-3 axis and releasing soluble VEGFR-2. Accordingly, our objective was to investigate the effect of an mTOR inhibitor, everolimus, on angiogenesis and lymphangiogenesis of HPV-negative TP53 mutant HNSCC. Everolimus treatment of HPV-negative HNSCC cell lines harboring a variety of TP53 mutations, significantly downregulated protein and mRNA levels of VEGF-A and VEGF-C. Moreover, everolimus downregulated HIF-1α protein levels suggesting a HIF-1alpha-dependent VEGF modulation. Interestingly, treatment of human microvascular and lymphatic endothelial cells (HMEC-1 and HMEC-1A, respectively) with everolimus was also associated with a significant reduction in cell proliferation, in vitro tube formation, and migration. Protein and mRNA levels of HIF-1α, VEGF-A, and VEGF-C were downregulated by everolimus treatment in both HMEC-1 and HMEC-1A cell lines. Taken together, our data suggest that everolimus prevents angiogenesis and lymphangiogenesis through the inhibition of HIF-1α, indicating a promising role for mTOR inhibitors in treating HPV-negative TP53 mutant HNSCC patients at high risk for recurrence. Citation Format: Md Maksudul Alam, Janmaris Marin Fermin, Mark Knackstedt, Mackenzie J. Noonan, Emily K. Daniel, Tara Moore-Medlin, Xiaohua Rong, Alok R. Khandelwal, Cherie-Ann O. Nathan. Everolimus inhibits angiogenesis and lymphangiogenesis to affect tumor growth in TP53 mutant HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3209.