Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of many antineoplastic agents, but the toxicity of individual drugs varies for reasons that are not well understood. Our laboratory has been studying the mechanisms of CIPN for over a decade.
We were initially involved in the CIPN characterization of the breast cancer drug, eribulin mesylate or HalavanTM which was launched by the FDA in Nov 2010. In the clinic, Halaven was unexpectedly found to induce less grade 2/3 neuropathy versus other microtubule agents (1,2).
We replicated this finding in mice showing that paclitaxel and ixabepilone produce more severe neuropathy in mice compared to eribulin, at their respective maximal tolerated doses (MTD)(3). We also found that eribulin caused less toxicity in animals with pre-existing neuropathy from an initial paclitaxel regimen (4).
In a continued collaboration with Eisai Inc, (the developers of HalavenTM) we have recently compared the plasma and peripheral nerve tissue distribution of eribulin, paclitaxel and ixabepilone. We found that despite eribulin’s lower propensity to induce neuropathy, its penetration into nervous tissue is cumulative and sustained to a greater degree than for other tubulin agents. We are currently exploring the recovery profile for the various CIPN deficits in collaboration with Drs. Mankowski and Polydefkis at John Hopkins. We are also collaborating with Drs. Feinstein, Jordan, and Wilson (at the Neuroscience Research Institute of University of California, Santa Barbara) to compare the axonal transport and microtubule binding profiles of microtubule agents.
In various other Pharma collaborations using our established paradigms, we are also evaluating novel pre-market chemotherapeutic agents for their propensity to induce neuropathy, as well as novel proprietary agents for their ability to reduce the development of neuropathy associated with chemotherapy, a property that could result in the development of a potential therapeutic for CIPN.
1. Vahdat LT, Garcia AA, Vogel C, Pellegrino C, Lindquist DL, Iannotti N, et al. Eribulin mesylate versus ixabepilone in patients with metastatic breast cancer: a randomized Phase II study comparing the incidence of peripheral neuropathy. Breast Cancer Res Treat 2013;140(2):341-51. [PubMed]
2. Cigler T, Vahdat LT. Eribulin mesylate for the treatment of breast cancer. Expert Opin Pharmacother 2010;11(9):1587-93. [PubMed]
3. Wozniak KM, Nomoto K, Lapidus RG, Wu Y, Carozzi V, Cavaletti G, et al. Comparison of neuropathy-inducing effects of eribulin mesylate, paclitaxel, and ixabepilone in mice. Cancer Res 2011;71(11):3952-62. [PubMed]
4. Wozniak KM, Wu Y, Farah MH, Littlefield BA, Nomoto K, Slusher BS. Neuropathy-inducing effects of eribulin mesylate versus paclitaxel in mice with preexisting neuropathy. Neurotox Res 2013;24(3):338-44. [PubMed]