Abstract LB-297: Characterization of novel hypoxia-activated prodrugs of irreversible pan-HER inhibitors

Abstract

Abstract Reversible HER1 (EGFR) inhibitors erlotinib and gefitinib are approved for use in non-small cell lung cancer (NSCLC), particularly demonstrating activity against tumors expressing mutant forms of HER1. Unfortunately, relapse invariably occurs in this patient population, with approximately half of patients having acquired an additional T790M mutation in HER1. Irreversible pan-HER inhibitors (BIBW2992, PF00299804) are under clinical evaluation in the context of NSCLC that has relapsed post-erlotinib/gefitinib treatment. However it is currently unclear whether these agents possess the therapeutic index in man necessary to gain approval in this setting (Regales et al., J. Clin. Invest. 2009, 119:3000-10), prompting the development of HER1T790M mutant-selective irreversible inhibitors (Zhou et al., Nature. 2009, 462: 1070-74). Hypoxia occurs in most human tumors and is associated with disease progression, resistance to conventional therapies and poor patient outcome. It can however be considered as an exploitable physiological target, as it supports tumor-selective bioreduction of prodrugs. We have developed hypoxia-activated prodrugs of irreversible pan-HER inhibitors as a strategy to broaden their therapeutic index. SN29966 is a prototype nitromethylaryl quaternary (NMQ) ammonium salt prodrug of an irreversible pan-HER inhibitor (SN29926), with masked cellular activity. Radiolytic reduction of SN29966 demonstrated fragmentation of the one-electron adduct to release SN29926 [kfrag 130 ± 10 s-1], and hypoxia-selective metabolism to SN29926 has been confirmed in all cell lines tested. SN32807 is the lead prodrug of this series, releasing the irreversible pan-HER inhibitor SN32793 in a hypoxia-dependent manner. In a panel of HER1/HER1T790M/HER2-expressing cell lines SN32807 showed hypoxia-dependent inhibition of proliferation (hypoxic/oxic IC50 ratios of 60, 11 and 20 in A431, H1975 and SKOV3 cells, respectively), a property SN32793 lacked (IC50 ratios 0.8-1.6). Tumor growth delay experiments (NIH-III nude mice) in large (500 mm3) HER1T790M-expressing H1975 tumor xenografts showed BIBW2992 (20 mg/kg, p.o. daily) failed to control tumor growth (i.e. progressive disease), with only a modest Tumor Growth Delay value of 35% [TGD % = [(T-C)/C]x100 where T and C are time to 4-fold increase in tumor volume from treatment day-1 for treated and control tumors, respectively]. In contrast, single-agent SN32807 (88 mg/kg; ip, q3dx8) demonstrated complete tumor responses in all animals during the treatment period (TGD value 246%; P<0.0005 vs controls; P<0.0005 vs BIBW-2992; log-rank test). Collectively the data indicates that SN32807 possesses a much improved therapeutic index relative to existing HER-family inhibitors, demonstrating marked activity against a HER1T790M-expressing erlotinib, gefitinib and BIBW2992 resistant tumor xenograft model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-297.