Abstract 3821: Targeted therapy for head and neck squamous cell carcinoma using the novel SMAC-mimetic birinapant

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is the most prevalent cancer affecting the upper aerodigestive tract, with an annual incidence of 600,000 patients and a five year survival of approximately 60% worldwide. Molecular mechanisms driving the development of HNSCC have recently begun to be discovered, with The Cancer Genome Atlas (TCGA) uncovering the genomic landscape of 279 cases of HNSCC. Alterations in cell death pathways were commonly found in the TCGA analysis, with ∼30% of samples harboring 11q13/22 amplifications and overexpression of genes encoding for Fas-associated death domain (FADD) and/or cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2). While overexpression of cIAP1 has been implicated in resistance to cytotoxic therapies, the role of FADD amplification as a target for therapy and in mechanisms of cell death is not well understood. Birinapant is a novel second mitochondria-derived activator of caspases (SMAC)-mimetic that targets and promotes degradation of cIAPs. Its clinical efficacy is currently being investigated in phase II trials of patients with ovarian cancer and leukemia. However, its preclinical and clinical efficacies have not been tested in HNSCC and genomic markers of sensitivity remain to be defined. Here we hypothesized that overexpression of FADD and cIAP1/2 could modulate birinapant sensitivity in HNSCC. To test this hypothesis, we have treated a panel of 11 HPV(-) and 8 HPV(+) HNSCC cell lines with birinapant alone and in combination with death agonists TNFα or TRAIL. UMSCC-46, an HPV(-) cell line which possesses high FADD expression, was the only cell line to reach half maximal inhibitory concentration (IC50) 72 hours post treatment with birinapant alone (IC50 = 10.7 nM); however, 8 of 11 HPV(-) cell lines and all 8 HPV(+) cell lines attained an IC50 (range: 0.1 - 794 nM) when treated with birinapant in combination with either TNFα or TRAIL. We further demonstrated that forced FADD overexpression in a previously resistant cell line (UMSCC-38) led to sensitization when treated with birinapant and TNFα. In vivo, two FADD/cIAP1 overexpressing murine xenograft models of HNSCC, UMSCC-46 and UMSCC-11B, were treated with birinapant at 15 mg/kg or 30 mg/kg every 3 days for a total of 10 treatments. The single modality regimen led to tumor growth inhibition and prolonged host survival. Additionally, combination treatment with birinapant 15 mg/kg and radiation 2Gy/day M-F for 2 weeks synergistically induced TNFα and led to a cure of animals bearing UMSCC-46 xenografts. Mechanistically, birinapant enhanced degradation of cIAP1 and modulated caspase apoptotic or MLKL necroptotic cell death markers in vitro and in vivo. These results suggest that patients harboring genomic alterations in FADD and/or cIAP overexpression may be candidates for treatment with birinapant and radiation. Supported by NIDCD intramural projects ZIA-DC-000073, and 74. Citation Format: Adeeb Derakhshan, Danielle Eytan, Grace Snow, Sophie Carlson, Anthony Saleh, Hui Cheng, Stephen Schiltz, Suresh Mohan, Shaleeka Cornelius, Jamie Coupar, Anastasia Sowers, Lydia Hernandez, James Mitchell, Christina Annunziata, Zhong Chen, Carter Van Waes. Targeted therapy for head and neck squamous cell carcinoma using the novel SMAC-mimetic birinapant. [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 3821.