Abstract 2055: The SMAC-mimetic Debio 1143 efficiently enhanced chemo and radiotherapy in head and neck squamous cell carcinoma models.

Abstract

Purpose/objectives: Resistance of tumor cells to chemotherapy (CT) or radiotherapy (RT)-induced apoptosis is a major problem in the treatment of head and neck squamous cell carcinoma (HNSCC), and highlights the need for new therapeutic strategies. The small molecule Debio 1143 (D1143) (a.k.a. SM-406 or AT-406) is a potent orally-active, monovalent Smac-mimetic designed to promote programmed cell death in tumor cells by blocking the activity of inhibitor of apoptosis proteins (IAPs) to create conditions in which apoptosis can proceed. This study aimed to test the efficacy of D1143 as a single agent and/or in combination with CT or RT in HNSCC models. Materials and methods: The effect of D1143 was assessed by the colony forming assay on a panel of HNSCC patient-derived xenograft (PDX) tumors and established cell lines. Tumor cells were incubated at various concentrations of D1143 (ranging from 0.1 to 30 μM) and treated with increasing doses of radiation or cisplatin. Cells were cultured for a minimum of 10 days before being fixed and stained. The number of surviving colonies was then recorded and compared to an untreated group. In parallel, various treatment sequences were tested, (before, during or post-irradiation) to determine the effect of D1143 on primary apoptosis (early, pre-mitotic apoptosis) and secondary apoptosis (late, post-mitotic reproductive cell death). The in vivo chemo/radiosensitizing effect of oral treatment with D1143 was further evaluated in nude mice bearing HNSCC tumor xenografts. Results: D1143 alone selectively inhibited colony formation of several PDX tumors and established cell lines. In addition, combination experiments found D1143 to be highly effective in enhancing cell death induced by RT or cisplatin. A synergistic effect of D1143 was observed in the majority of the tested cell lines treated by RT, whereas D1143 enhanced the activity of cisplatin in a subset of tumor cells. Interestingly, the radiosensitizing effect of D1143 was preeminent when cells were co-incubated with D1143 24 hours after irradiation, showing that D1143 efficiently impacts late apoptosis due to mitotic catastrophe and/or other cell death events that arise after irradiation. In mice bearing HNSCC radio-resistant tumors, D1143 given orally in combination with RT delayed tumor growth for more than 40 days when compared to RT only and for more than 60 days when compared to vehicle only. In addition, oral administration of D1143 showed additive to synergistic activity when combined with intravenous cisplatin in nude mice bearing PDX HNSCC tumors. Conclusion: Altogether, these results show that D1143 exhibits activity as a single agent and can potentiate the effects of chemo/radiotherapy in HNSCC models indicating that D1143 has a promising therapeutic potential for the treatment of HNSCC. Citation Format: David Viertl, Florence Perillo-Adamer, Stefania Rigotti, Jean-Luc Muralti, Hélène Maby-El Hajjami, Anne Vaslin, Grégoire Vuagniaux, Oscar Matzinger. The SMAC-mimetic Debio 1143 efficiently enhanced chemo and radiotherapy in head and neck squamous cell carcinoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2055. doi:10.1158/1538-7445.AM2013-2055

Model‐Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck

“…The PK model-derived median free average daily concentration of xevinapant at steady-state (C avg,ss ) at the 200-mg/day dose in humans was similar to the estimated 90% inhibitory concentration for cIAP1 inhibition. Additionally, the range of free C avg,ss with 200-mg/day dosing in humans overlapped with the estimated C avg,ss at the efficacious dose range of 30-100 mg/kg/day (5 days on/2 days off ) in SCCHN models as monotherapy or in combination with RT 15,20,35 (Table 2). Thus, pharmacological contextualization of the population PK model-derived human exposure distributions in relation to vitro potency data and the exposure range associated with in vivo antitumor activity in the mouse xenograft efficacy model supported the assessment of the 200-mg/ day dose being pharmacologically robust for clinical evaluation of efficacy and safety.…”

“…Furthermore, some cell lines are sensitive to xevinapant alone, whereas others require another apoptotic trigger, such as RT or CT with no link to the extent or duration of cIAP1 inhibition. Likewise, xevinapant only has antitumor activity as monotherapy in some in vivo xenograft models in mouse, whereas most models, including the SCCHN models, requiring xevinapant in combination with RT or CT for antitumor activity 14,15,20 . No pharmacokinetic (PK)/PD data are available in SCCHN xenograft models.…”

“…Likewise, xevinapant only has antitumor activity as monotherapy in some in vivo xenograft models in mouse, whereas most models, including the SCCHN models, requiring xevinapant in combination with RT or CT for antitumor activity. 14,15,20 No pharmacokinetic (PK)/PD data are available in SCCHN xenograft models. In the MDA-MB-231 breast cancer xenograft model, where xevinapant has monotherapy activity, the dose that achieved maximal antitumor activity in several mouse models (100 mg/kg/ day) is associated with nearly maximal cIAP1 inhibition during the treatment period.…”

Inhibiting the inhibitors: Development of the IAP inhibitor xevinapant for the treatment of locally advanced squamous cell carcinoma of the head and neck

“…In tumor samples from patients with SCCHN, xevinapant + cisplatin or carboplatin induced caspase-3–dependent apoptosis [ 64 ]. In SCCHN cell lines and mouse xenograft models, xevinapant exhibited limited activity as a single agent and synergistic/additive activity with chemotherapy and radiotherapy [ 62 , 65 ].…”