Abstract 3336: The Smac Mimetic Birinapant Synergistically Induces Apoptosis in Combination with Type I Interferons and GM-CSF.
Authors: Benetatos Christopher A. , Burns Jennifer M. , Borden Ernest C. , Lindner Daniel , Mitsuuchi Yasuhiro , Mckinlay Mark A. , Kapoor Gurpreet Singh , Neiman Eric M. , Seipel Martin E. , Yu Guangyao , Graham Martin , Weng David , Condon Stephen M. , Begley C. Glenn , Chunduru Srinivas 
Published: August 2014

Abstract
The Inhibitor of Apoptosis (IAP) protein family is able to inhibit cell death and promote survival signaling triggered by a wide variety of stimuli. Two members of this family in particular, cIAP1 and cIAP2, play key roles in enabling tumor necrosis factor alpha (TNFα)-induced nuclear factor-kappa beta (NF-kB) activation and inflammatory responses. Birinapant (TL32711) is a bivalent Smac Mimetic that antagonizes multiple IAP family members resulting in the conversion of TNFα-induced survival signaling into an apoptotic response, an effect which is more prominent in tumor cells than their normal counterparts. Combining birinapant with agents capable of increasing the levels of TNFα in the tumor microenvironment represents a novel approach to cancer treatment. We have tested the ability of interferon-alpha/-beta (IFN-α, IFN-β) and granulocyte macrophage colony stimulating factor (GM-CSF), both known to be immunomodulatory agents, for their ability to stimulate TNFα production by peripheral blood mononuclear cells (PBMC). Treatment with each cytokine induced the production of TNFα by cultured PBMC as measured by ELISA. Supernatants of IFN-α/-β and GM-CSF-treated PBMC cultures were able to sensitize resistant tumor cells to Smac Mimetics in a TNFα-dependent manner. Furthermore, the combination of birinapant and either IFN-β or GM-CSF synergistically inhibited the development of RENCA tumors in a syngeneic mouse prevention model. Due to the highly aggressive nature of the syngeneic tumors, this model is performed by simultaneous implantation of tumor cells and initiation of dosing of test agents. Activity in this model is measured by prevention of tumor outgrowth. Birinapant in combination with IFN-β resulted in only 5 of 18 measurable tumors, versus 19 of 20 tumors in vehicle-treated mice, 16 of 20 tumors in IFN-β alone-treated mice and 13 of 20 tumors in birinapant alone-treated mice. In addition, when tumor growth occurred it was delayed in mice treated with the combination. Similarly, the birinapant and GM-CSF combination treatment resulted in 9 of 20 tumors, versus 20 of 20 tumors in the vehicle-treated mice, 20 of 20 tumors in the GM-CSF alone-treated mice, and 16 of 20 tumors in the birinapant alone-treated mice. In addition when tumors did develop in the combination-treated mice, their growth was substantially delayed: 4 of 10 mice treated with the combination of birinapant and GM-CSF were still on study on day 85 post initiation - approximately 40 days post dosing - with no measureable tumor. The combination of birinapant with immunomodulatory agents that induce TNF represents a potential novel therapeutic strategy.
Citation Format: Christopher A. Benetatos, Jennifer M. Burns, Ernest C. Borden, Daniel Lindner, Yasuhiro Mitsuuchi, Mark A. Mckinlay, Gurpreet Singh Kapoor, Eric M. Neiman, Martin E. Seipel, Guangyao Yu, Martin Graham, David Weng, Stephen M. Condon, C. Glenn Begley, Srinivas Chunduru. The Smac Mimetic Birinapant Synergistically Induces Apoptosis in Combination with Type I Interferons and GM-CSF. [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 3336. doi:10.1158/1538-7445.AM2013-3336