Abstract 4438: Comparison of neuropathy-inducing effects of eribulin versus paclitaxel in mice

Abstract

Abstract Eribulin (referred to as E7389 in the mesylate salt form) is a structurally simplified analog of the potent anticancer agent halichondrin B. Eribulin inhibits microtubule dynamics via a mechanism that is distinct from that of other tubulin-targeting drugs. Eribulin has recently shown activity in Phase III trials for advanced metastatic breast cancer. Current standard treatment for breast cancer includes paclitaxel, whose major dose-limiting toxicity is peripheral neuropathy. This study was conducted to directly compare the neuropathy-producing effects of paclitaxel versus eribulin in mice. Maximum tolerated dose (MTD) levels using a 3x/week intravenous regimen (Q2D x 3) for 2 weeks, were determined for each compound. Neuropathy studies were then conducted in mice dosed at the respective MTDs or fractions thereof (0.75, 0.5 and 0.25 of the MTD), or with vehicle control. Mice were evaluated for nerve conduction velocity (NCV) and amplitude in caudal and digital nerves 24 hr after their last treatment. Sciatic nerves and dorsal root ganglia (DRG) were subsequently removed for pathological assessment. After 2 weeks dosing with paclitaxel, clear dose-dependent decreases in caudal NCV and amplitude were evident. At MTD (30 mg/kg), paclitaxel caused a significant reduction in caudal NCV compared to control (18 +/− 3.8%; p<0.01), while both MTD and 0.75 MTD doses caused significant reduction in caudal amplitude compared to control (63.5 +/− 4.8% and 48.8 +/− 4.2%, respectively; p<0.001). Both MTD and 0.75 MTD paclitaxel also caused significant reduction in digital nerve amplitude (62.8 +/− 4.1 % and 35.2 +/− 4.3 %, p<0.001 and p<0.05 respectively). In contrast, after 2 weeks dosing with eribulin, there were no decreases in caudal or digital NCV or amplitude at any dose, including the MTD (1.75 mg/kg). Microscopic examination revealed that paclitaxel induced moderate to severe dose-dependent pathological changes in sciatic nerve and DRG at doses of 0.5 MTD or higher. Eribulin produced some mild pathological changes in DRG neurons and sciatic nerve, which although less severe, were clearly evident at the 0.75 MTD and MTD doses. In conclusion, eribulin administered to mice intravenously at doses up to and including the MTD, during an intensive two week regimen induced no significant reduction in nerve conduction velocity or amplitude in caudal and digital nerves, findings that contrast markedly with the significant decreases in nerve conduction velocity and amplitude induced by paclitaxel. In addition, eribulin caused less severe morphological changes in DRG and sciatic nerves at equivalent MTD-based doses. Overall, these preclinical findings suggest that eribulin may be less likely to induce neuropathy than paclitaxel. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 4438.