Cellular Mechanisms of Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) and the associated pain represent a clinically relevant limit to patient treatment with anti-cancerdrugs. Currently, there is no effective treatment for CIPN. Enhanced excitability of peripheral sensory neurons is thought to contribute to the generation and progression of CIPN. By directly affecting membrane excitability, CIPN-causing chemotherapy drugs may enhance neuronal activity eventuating neuroexcitotoxicity and neuropathy. Whether a change in peripheral sensory neuron excitability is an early formative event of CIPN, though, is unknown. To date there have been few studies of peripheral sensory neurons directly investigating the cellular and molecular mechanisms by which chemotherapy drugs cause CIPN. Performing such experiments in mammals has been complicated by the heterogeneity of sensory neurons within the dorsal root ganglion, the site in mammals where nociceptors reside, and limitations in the experimental tractability of these complicated organisms. The group of PIs submitting this proposal is expert in investigating the cellular mechanisms underlying sensory transduction in peripheral sensory neurons in Drosophila, rodents, and humans. The current proposal combines complementary expertise in a relevant rodent model of peripheral pain with an unbiased approach in a model organism to investigate the cellular and molecular mechanisms of CIPN. The goals of this proposal are to demonstrate that understanding gleaned from investigating the effects of CIPN-causing chemotherapy drugs on peripheral sensory neurons in a simple model organism can be used in a rational manner to direct more complicated studies in a relevant mammalian system in order to provide a powerful means for determining the cellular and molecular mechanism of CIPN and facilitate the discovery of new analgesics for the treatment of CIPN. Our preliminary results suggest the novel hypothesis that CIPN is a result of the direct effect of chemotherapy drugs on the sensory transduction machinery of peripheral nociceptors. We accomplish the goals of this R21 by testing three specific aims: Aim 1; to characterize a novel Drosophila model of CIPN that will be employed to direct experiments in relevant mammalian models of pain. Aim 2: To define the cellular and molecular mechanisms that underlie the effects of vinblastine and paclitaxel on sensory neuron function. And Aim 3: To investigate whether peripheral application of vinblastine and paclitaxel can induce CIPN in mammals. The importance and significance of the worked proposed here is supported by the recent funding announcement from the NIH/NCI: PA-12-083, 'Biomechanisms of Peripheral Nerve Damage by Anti-Cancer Therapy (R21)'. It is expected that the successful completion of the experiments described in this proposal will provide key understanding of fundamental mechanisms that underlie CIPN and establish a research team well-positioned to use rational and translational approaches to develop novel treatment strategies to counter CIPN. PUBLIC HEALTH RELEVANCE: Chemotherapy-induced peripheral neuropathy (CIPN) is clinically relevant pain syndrome observed in patients undergoing chemotherapy that is a significant burden to patients and limits the dosage of anti-cancer drugs. There are no effective treatments for CIPN at this time. A more complete understanding of the causes of CIPN should allow development of analgesics for CIPN allowing for more effective anti-cancer drug treatments.