Abstract 2755: Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of NSC750854, a sulfamated purine analog with a distinctive anticancer activity profile.

Abstract

Abstract Introduction: NSC750854 [3,4-dihydroxy-5-purin-9-yloxolan-2-yl)methyl sulfamate] is a purine analog with an activity profile substantially different from that of other anticancer purines. Unlike purine analogs used as anticancer agents, it does not have any substituents on the purine base. Because of the 5’-sulfamate on its sugar component, it cannot be phosphorylated. Initial mechanistic studies have shown that it does not interact with the RNA/DNA pathways typically affected by purine analogs, and further work on target identification is underway. Methods: NSC750854 was tested against the PPTP's in vitro cell line panel at concentrations ranging from 1.0 nM to 10.0 μM using the PPTP's standard 96 hour exposure period. It was tested against PPTP solid tumor xenografts using a dose of 5 mg/kg administered by the intraperitoneal (IP) route daily for 5 days repeated at day 15. Results: The median relative IC50 (rIC50) value for the PPTP cell lines was 32 nM, with a range from 11 nM (MOLT-4) to 124 μM (CHLA-258). NSC750854 demonstrated consistent cytotoxicity across all of the PPTP cell lines, with Relative In/Out% values near -100% for each of the cell lines. The acute lymphoblastic leukemia (ALL) cell lines were more sensitive to NSC750854 than non-ALL cell lines. NSC750854 showed no dependence on TP53 for its cytotoxic effect, and TP53 mutated cell lines had nominally lower rIC50 values compared to wildtype cell lines. NSC750854 was well tolerated in vivo, with only a 1.7% toxicity rate in treated animals, similar to that observed for control animals (0.7%). NSC750854 induced significant differences in EFS distribution compared to control in 26 of 30 (87%) of the evaluable solid tumor xenografts. NSC750854 induced tumor growth inhibition meeting criteria for intermediate or high EFS T/C activity (requiring EFS T/C > 2) in 14 of 29 (48%) evaluable solid tumor xenografts. Objective responses were observed in 11 of 30 xenografts. Responses were observed for multiple histotypes, including rhabdoid tumors, Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and neuroblastoma. While some of the xenografts that were responsive to NSC750854 have also shown responsiveness to other cytotoxic agents (e.g., KT-10, KT-16, and Rh10 and to a lesser extent D456 and D645), other responsive models have shown limited sensitivity to most agents against which they've been tested (e.g., BT-29 and CHLA-79). Conclusions: NSC75084 shows high activity at a well-tolerated dose against multiple pediatric solid tumor xenografts, including activity against highly resistant models. Data mining activities are ongoing to generate hypotheses regarding molecular characteristics associated with responsiveness to NSC750854. (Supported by award NO1-CM-42216 from the NCI). Citation Format: Malcolm Smith, Min Kang, Patrick Reynolds, Richard Gorlick, Anders Kolb, John Maris, Stephen Keir, Catherine Billups, Raushan Kurmasheva, Peter Houghton, Jerry Collins. Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of NSC750854, a sulfamated purine analog with a distinctive anticancer activity profile. [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 2755. doi:10.1158/1538-7445.AM2013-2755