Identification of susceptibility to chemotherapy induced peripheral neuropathy using patient stem cell derived sensory neurons Current understanding of the mechanisms responsible for chemotherapy induced peripheral neuropathy (CIPN) is extremely limited and more importantly, there is no way of identifying who is at risk. In this proposal, we will test the utility of an in-vitro model of CIPN using human neurons generated from patient-derived stem cells for the study of CIPN risk. Sensory neurons, the neurons most commonly affected in CIPN, will be generated from iPSC lines generated from patients treated with the chemotherapeutic paclitaxel who did, or did not, develop CIPN. The susceptibility of these neurons to paclitaxel-induced neurotoxicity will be measured to determine whether neurons from individuals with CIPN are more vulnerable to chemotherapeutic neurotoxicity than those from their age, gender and dose matched controls who did not develop CIPN. The sensory neurons will also be exposed to other classes of chemotherapeutic agents, which also cause peripheral neuropathy despite distinct antineoplastic mechanisms, to determine whether sensory neuron susceptibility to chemotherapy-induced toxicity is generic or specific to certain classes of drug. These findings could contribute to identifying patients at risk for CIPN prior to their treatment and understanding the factors which contribute to CIPN susceptibility.
Chemotherapy induced peripheral neuropathy (CIPN) is a debilitating, untreatable side effect of chemotherapy which affects 40-70% of the 15.5 million cancer survivors in the United States alone. Why certain chemotherapy patients develop CIPN and others do not is currently unknown. This proposal will determine whether in-vitro phenotyping of patient iPSC derived neurons can recapitulate patient risk for CIPN in order to help advance the study of CIPN risk factors.
