Birinapant (TL32711), a Small Molecule Smac Mimetic, Induces Regressions in Childhood Acute Lymphoblastic Leukemia (ALL) Xenografts That Express TNF alpha and Synergizes with TNF alpha in Vitro - A Report From the Pediatric Preclinical Testing Program (PPTP)

3565 Introduction: Birinapant is a small molecule mimetic of Smac that potently and specifically antagonizes multiple inhibitors of apoptosis proteins (IAPs). Birinapant rapidly degrades cIAPs and enables cytokines (TNFα, TRAIL) to activate the extrinsic apoptosis pathway, while it rapidly turns off the canonical NF-κB survival pathway, causing cancer cell death. Preclinical studies using adult cancer models have shown that birinapant causes tumor regressions as a single agent in selected models and that it has potent antitumor activity when combined with chemotherapies and death receptor ligands. Methods: Birinapant was evaluated against the 23 cell lines of the PPTP in vitro panel (including 1 AML and 5 ALL lines) using 96 hour exposure at concentrations from 1.0 nM to 3.0 μM, both as a single agent and in combination with TNFα (10 ng/mL) or TRAIL (10 ng/mL). Birinapant was tested against 2 PPTP solid tumor xenografts (rhabdomyosarcoma, Rh30; Ewing, CHLA-258), an anaplastic large cell lymphoma (ALCL) xenograft (Karpas-299), and 3 B-precursor ALL xenografts (ALL-2, ALL-17, & ALL-19) at a dose of 30 mg/kg administered by the intraperitoneal route using a Q3 day × 5 schedule. Gene expression data for the PPTP cell lines and xenografts was available using both Affymetrix U133 Plus 2.0 and Agilent SurePrint G3 arrays. Results: Birinapant demonstrated limited single agent activity (median relative IC50 (rIC50) > 3 μM), with only the AML cell line Kasumi-1 showing Relative In/Out% (Rel I/O%) values < 0% with rIC50 of 37 nM. Marked potentiation of birinapant was observed for a subset of cell lines with the addition of TNFα or TRAIL. The 5 ALL cell lines showed a median rIC50 value of 3.6 nM for birinapant in combination with TNFα, with Rel I/O% values between −50% and −100% (indicative of a profound cytotoxic effect). Four of 5 ALL cell lines showed little or no potentiation of birinapant effect with the addition of TRAIL. Among solid tumor cell lines, potentiation of birinapant effect was observed ...