Pediatric preclinical testing program (PPTP) evaluation of the Bcl-2 inhibitor ABT-263

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Background: ABT-263 is a potent (K_i < 1 nM) small-molecule BH3 mimetic that inhibits the antiapoptotic proteins Bcl-2, Bcl-X_L and Bcl-w. The structurally related Bcl-2 inhibitor ABT-737 exhibits single-agent cytotoxicity against lymphoma, small-cell lung carcinoma, acute lymphoblastic leukemia (ALL), and neuroblastoma cell lines and displays synergistic cytotoxicity with chemotherapeutics and radiation.

Methods: The PPTP includes an in vitro panel (n=27) as well as panels of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood ALL. ABT-263 was tested against the in vitro panel at concentrations from 1 nM to 10 microM and against the in vivo tumor panels at a dose of 100 mg/kg PO daily for 21 days. Three measures of antitumor activity were used: 1) response criteria modeled after the clinical setting [e.g., partial response (PR), complete response (CR), etc.]; 2) treated to control (T/C) tumor volume at day 21; and 3) a time to event (4X increase in tumor volume or 25% hCD45 in peripheral blood for ALL panel) measure based on the median EFS of treated and control lines (intermediate activity required EFS T/C > 2, and high activity additionally required a net reduction in median tumor volume at the end of the experiment).

Results: ABT-263 was active against approximately one-half of the 23 cell lines of the PPTP in vitro panel. The median EC₅₀ for all of the lines in the panel was 1.8 microM. There was a trend for lower EC₅₀ values for the ALL panel compared to the remaining PPTP in vitro cell lines (median EC₅₀ 0.4 microM versus > 10 microM, p=0.04), and the ALL line RS4;11 had the lowest EC₅₀ (0.06 microM). ABT-263 induced significant differences in EFS distribution in 9 of 35 (26%) of the solid tumor xenografts, and in 4 of 6 (67%) of the evaluable ALL xenografts. Using the PPTP time to event measure of efficacy, ABT-263 had an intermediate level of activity against 1 of 35 evaluable solid tumor xenografts (a neuroblastoma xenograft with EFS T/C of 2.0) and did not induce either PRs or CRs in the solid tumor panels. Response assessments for the 6 evaluable xenografts in the ALL panel included 3 CRs, one that was maintained for the 3 weeks of treatment and two that were maintained for an additional 3 weeks following treatment cessation.

Conclusions: ABT-263 demonstrated in vitro activity against a range of cell lines, with the ALL cell lines showing the greatest sensitivity. ABT-263 demonstrated limited single agent in vivo activity against the PPTP’s solid tumor panels. However, high levels of activity were observed for xenografts in the ALL panel. Further work is needed to evaluate the activity of ABT-263 in combination with standard chemotherapy agents and to evaluate associations between the molecular characteristics of the PPTP’s preclinical models and their responsiveness to ABT-263. (Supported by NCI NO1CM42216)