Abstract 1030: Targeting tumor-stroma metabolic symbiosis for head and neck cancer therapy

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy affecting 40,000 cases in the USA annually. Despite aggressive therapies HNSCC is associated with less than a 50% 5-year survival rate. Limited treatment options and high morbidity necessitate the development of new treatments. HNSCC tumors frequently consist of up to 80% tumor-associated fibroblasts (TAFs). We reported that tumor associated fibroblasts (TAFs) facilitate HNSCC progression. However, the molecular mechanisms that facilitate TAF-mediated tumor growth and metastasis remain unknown. Unlike normal cells, malignant cells often display increased glycolysis, even in the presence of oxygen; a phenomenon known as the Warburg effect. As a consequence, there is an increase in lactic acid (LA) production. It has been reported that HNSCC tumors have high LA levels that correlate with reduced survival. The mechanisms whereby HNSCC tumors survive in highly acidic conditions remain unknown. We previously reported that TAF-secreted hepatocyte growth factor (HGF) facilitates HNSCC progression. Here we demonstrate that TAF-secreted HGF regulates HNSCC glycolysis and increases basic fibroblast growth factor (bFGF) secretion from HNSCC. Further, HNSCC-secreted bFGF regulates mitochondrial oxidative phosphorylation (OXPHOS) in TAFs. Inhibition of c-Met by PF-02341066 or knockdown by siRNA decreases glycolysis and bFGF expression in HNSCC. In addition, inhibition of FGFR by AZD-4547 decreased OXPHOS and HGF expression in TAFs. Thus, HNSCC and TAFs engage in reciprocal signaling through paracrine effects of HGF and bFGF. Combined treatment with AZD-4547 and PF-02341066 significantly inhibited TAF-induced proliferation of HNSCC in vitro compared to the vehicle control treated cells. For the first time, we tested FGFR inhibitor AZD-4547 in combination with c-Met inhibitor PF-02341066 both in vitro and in vivo xenograft models. The combination treatment significantly inhibited proliferation of HNSCC in vitro and effectively reduced HNSCC tumor growth compared to either agent alone in vivo (p<0.001). Our cumulative findings underscore the therapeutic potential of combinatorial treatment with PF-02341066 and AZD-4547 in HNSCC. Citation Format: Dhruv Kumar, Vikalp Vishwakarma, Jacob New, Radhika Joshi, Fangchen Lin, Sumana Dasari, Wade Gutierrez, Hemant Chavan, Ossama Tawfik, Shary Shelton, Yelizaveta Shnayder, Kiran Kakarala, Terance Tsue, Douglas Girod, Bennett Van Houten, Partha Kasturi, Sufi M. Thomas. Targeting tumor-stroma metabolic symbiosis for head and neck cancer therapy. [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 1030.