Axonal transport and chemotherapy induced peripheral neuropathy

ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and debilitating sequela for many cancer patients. For some patients this complication prevents optimal therapy and so jeopardizes the chance for a cure, while many patients develop permanent, untreatable pain and severe sensory deficits that seriously compromise quality of life for cancer patients and survivors. The mechanisms that cause axon degeneration and sensory symptoms in CIPN are just beginning to be defined, and it is not yet clear whether the mechanisms that underlie CIPN can be biologically resolved from anti-neoplastic efficacy of chemotherapy. Against this backdrop, our previous studies under this grant have demonstrated a central role for increased axonal Ca+2 and activation of Ca+2-dependent calpain proteases in CIPN. Building on these findings we will identify the processes linking together 1) the direct effects of paclitaxel or other chemotherapies on microtubules, 2) activation of molecules implicated in axon destruction, plus the loss of compounds that promote axon survival and 3) opening of Ca+2 channels located within the long axons. Our studies make use of rodent sensory neurons in compartmented cultures, immunocompetent mice with paclitaxel-sensitive breast cancer, and new human iPSC-derived sensory neuron cultures prepared from patients with severe CIPN or from patients resistant to CIPN. Using these innovative approaches we will identify therapeutic targets for treating CIPN without compromising the anti-neoplastic efficacy of paclitaxel and we will develop novel therapeutic compounds. Since the process of axon degeneration in CIPN is similar to that seen in diseases including hereditary neuropathy, ALS, and Alzheimer’s disease, our insights and therapeutic approaches will advance treatment for many additional debilitating diseases.