Abstract 5464: Distinct effects of eribulin on axonal microtubule composition and modifications relative to paclitaxel, vincristine and ixabepilone in preclinical models: correlations with lower levels of eribulin-induced peripheral neuropathy (2014)

Abstract Microtubule targeting agents (MTAs) are widely used anti-cancer drugs. They suppress microtubule dynamics, prevent complete spindle formation and induce cell cycle arrest and cell death in rapidly dividing tumor cells. Unfortunately, systemic administration of different MTAs can also lead to significant side effects including debilitating, dose-limiting peripheral neuropathy. Interestingly, different MTAs vary with respect to the frequency and severity of neuropathic symptoms. MTAs are hypothesized to induce neuropathy by disrupting the normal functions of microtubules, including maintenance of elongated axonal structures and mediating axonal transport of cellular components between the cell body and nerve endings. Consistent with this notion, different MTAs vary in their mechanisms of microtubule binding and regulation of microtubule dynamics. To begin testing the hypothesis that differing molecular mechanisms underlie the variable nature of peripheral neuropathy, we examined biochemical changes in microtubule composition, modification and the levels of selected microtubule associated proteins, all of which affect microtubule dynamics and microtubule action. We compared sciatic nerves from mice treated with a Q2Dx3 schedule for 2 weeks at the maximum tolerated doses of paclitaxel, ixabepilone, vincristine or eribulin. Sciatic nerves were fixed, sectioned and immunostained with antibodies directed against α-tubulin, acetylated-tubulin and tyrosinated tubulin as well as the microtubule (+) end binding proteins EB1 and EB3. Images, acquired by confocal microscopy, were analyzed with Imaris software to quantitate drug-induced changes. The most marked effects were observed with eribulin treatment. Sciatic nerves from eribulin treated mice exhibited ∼2.5 fold increase in α-tubulin signal, ∼12 fold increase in acetylated tubulin signal, ∼1.5 fold increase in tyrosinated tubulin signal and ∼2 fold increase in EB1 signal. No significant change was observed for EB3. In contrast, with the exception of a ∼5 fold increase in the acetylated tubulin signal in paclitaxel treated mice, no other statistically significant effects were observed with paclitaxel, ixabepilone or vincristine treatment. The data suggest that the mechanisms of eribulin action alter normal axonal cell biology, leading to increased abundance of tubulin and EB1. Increased levels of acetylated tubulin observed with paclitaxel and eribulin treatment suggests increased microtubule stabilization. Taken together, the data suggest that eribulin affects neuronal microtubules differently than paclitaxel, ixabepilone or vincristine, correlating with its relatively low level of induced peripheral neuropathy. We gratefully thank Eisai Inc. for support of this research. Citation Format: Sarah J. Benbow, Brett M. Cook, Krystyna M. Wozniak, Barbara S. Slusher, Bruce A. Littlefield, Leslie Wilson, Stuart C. Feinstein, Mary A. Jordan. Distinct effects of eribulin on axonal microtubule composition and modifications relative to paclitaxel, vincristine and ixabepilone in preclinical models: correlations with lower levels of eribulin-induced peripheral neuropathy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5464. doi:10.1158/1538-7445.AM2014-5464