Abstract 5503: Microtubule-targeting agents induce differential myelinated axon degeneration in a mouse model of peripheral neuropathy

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Microtubule-targeting agents (MTAs) have proven useful in treating many types of cancers. However, their efficacy continues to be limited by peripheral neuropathy, a painful and potentially dose-limiting side effect. While the mechanisms of MTA-induced neuropathy remain unclear, evidence suggests that peripheral nerve degeneration contributes to altered nerve activity and neuropathic pain. Recent electrophysiological studies in mice revealed that paclitaxel and ixabepilone reduced peripheral nerve conduction velocity and amplitude, while eribulin, an MTA with a lower incidence of severe peripheral neuropathy, showed no change in these parameters. Here, we sought to test the hypothesis that MTA-induced peripheral neuropathy in mice positively correlates with axon degeneration. We compared the effects of four MTAs with varying incidences of severe neuropathic symptoms (vincristine > ixabepilone = paclitaxel > eribulin). Naive adult mice were treated at their maximum tolerated dose of each drug (or vehicle) on a Q2Dx3 schedule for 2 weeks. Sciatic nerves were extracted, fixed, sectioned, and visualized by immunofluorescence confocal microscopy. Morphological changes were quantified using Imaris software. Paclitaxel and eribulin resulted in significantly lower myelinated axon densities of 172 ± 14.5 and 264 ± 18.0 axons per 100 μm2 compared to vehicle controls of 371 ± 14.2 and 366 ± 19.3 respectively (mean ± SEM, P < 0.001). Paclitaxel and eribulin also increased the percentage of collapsed nerve fibers, which were identified by fragmented and/or contracted myelin sheaths coupled with a loss of phospho-neurofilament protein signal from the associated axons. The percent of collapsed nerve fibers was 2.2% for eribulin (vs. 0.32% vehicle; P < 0.05) and 6.6% for paclitaxel (vs. 0.21% vehicle; P<0.001). For paclitaxel, nerve fiber collapse occurred more frequently in distal than in proximal nerve sections (P < 0.01). We also observed a unique myelin “halo” morphology in eribulin treated nerves that was not found in any other condition. Surprisingly, vincristine and ixabepilone did not induce detectable nerve degeneration, even though both drugs exhibit a high incidence of severe peripheral neuropathy. Our results indicate that although significant nerve degeneration is present after two weeks of treatment with some MTAs, the extent of these changes does not correlate with the clinical incidence of severe neuropathy. Therefore, although degenerative changes in peripheral nerves may contribute to nerve dysfunction in MTA-induced peripheral neuropathy, especially in the cases of paclitaxel and eribulin, they do not appear to be the only factor underlying this condition. We conclude that additional mechanisms of MTA-induced peripheral neuropathy likely exist which may not be directly related to axonal degeneration. We gratefully thank Eisai Inc for support of this research. Citation Format: Brett M. Cook, Sarah J. Benbow, Krystyna M. Wozniak, Barbara S. Slusher, Bruce A. Littlefield, Leslie Wilson, Stuart C. Feinstein, Mary Ann Jordan. Microtubule-targeting agents induce differential myelinated axon degeneration in a mouse model of 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 5503. doi:10.1158/1538-7445.AM2014-5503