A debilitating and dose-limiting side effect faced by cancer patients treated with the chemotherapeutic agent paclitaxel is peripheral neuropathy, for which there are currently no approved interventions or preventative treatments. Paclitaxel is one of the most widely used chemotherapy drugs, used in treatment of breast, ovarian and lung cancer, among others. Paclitaxel binds along the length of microtubules and stabilizes them, which interferes with mitotic spindle dynamics and causes apoptosis in dividing cells. Though they do not divide, neurons are also susceptible to paclitaxel, and paclitaxel exposure leads to axonal degeneration. A roadblock to the identification of therapeutics for the paclitaxel-induced peripheral neuropathy is the current lack of mechanistic understanding of the neuronal damage. The goal of the proposed research is to advance understanding of the cell biological mechanisms underlying axonal degeneration caused by paclitaxel.
The aims of this proposal are: 1) To test the hypothesis that microtubule stabilization is the primary cause of paclitaxel neurotoxicity; 2) To investigate if paclitaxel neurotoxicity arises from biochemical alterations t microtubules;3) To investigate the potential role of axonal transport defects in paclitaxel neurotoxicity. Experiments will be carried out in cultured mammalian sensory neurons, the cell type relevant to the clinical problem of peripheral neuropathy and a system amenable to cell biological manipulations. Completion of the aims will yield mechanistic insight into the contribution of microtubule alterations and axonal transport impairment to paclitaxel-induced axonal degeneration, which may facilitate development of ameliorative treatments for paclitaxel-induced peripheral neuropathy. Overall, this work will develop understanding of the relationship between the dynamics of the microtubules and axonal transport machinery and their roles in neuronal health and survival.
This proposal investigates the cellular mechanisms underlying the neurotoxicity of the chemotherapeutic agent, paclitaxel, for which peripheral neuropathy is often a debilitating complication. Understanding the mechanisms responsible for the neuronal damage caused by paclitaxel may provide a foundation for development of therapeutic interventions for paclitaxel-induced peripheral neuropathy.