Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect that causes morbidity and limits the dose of chemotherapy allowed to treat cancers. Of those receiving neurotoxic chemotherapy, approximately 30-40% of patients develop CIPN, yet the risk factors for developing this are poorly understood. The goal of this project is to test whether susceptibility to CIPN can be predicted in vitro by employing our novel CIPN-in-a-dish neurotoxicology assay that uses iPSC- derived sensory neuron from patient samples. In the first Specific Aim, sensory neurons (iSN) will be derived from patients with Charcot-Marie-Tooth disease (hereditary peripheral neuropathy). First, the CIPN-in-a-dish assay will be used to compare susceptibility between iSN from CMT patients and healthy controls. Subsequently CMT samples will have their deleterious gene mutation corrected using gene-editing technology (CRISPR/Cas) and CIPN susceptibility will be compared between the pathologic iSN and gene-corrected iSN. In the second Specific Aim, iSN will be derived from a cohort of patients with breast cancer that have received standard adjuvant paclitaxel chemotherapy. Again using the CIPN-in-a-dish assay, iSN from patients that have clearly developed CIPN from paclitaxel will be compared in a blinded fashion with patients that clearly have not. These studies will serve two important functions: 1) they are a ?proof-of-principle? study that determines whether this approach using patient samples can be used to predict CIPN in individual patients, 2) a hypothesis-generating study wherein patient samples will allow for directed studies of mechanisms of CIPN susceptibility. The potential future application of this technology will be to use a patient's own neurons to determine their susceptibility to the neurotoxic effects of specific chemotherapy, thus allowing for personalized precision medicine for the patient with cancer.
Peripheral neuropathy occurs in 30-40% of patients who are treated with neurotoxic chemotherapy and results in dose-limiting pain, numbness and weakness that can lead to long term illness. This proposal aims to conduct a ?proof-of-concept? study to investigate whether patient-specific adult stem cell-derived neurons can predict the susceptibility to chemotherapy-induced peripheral neuropathy. The ability to predict chemotherapy-induced peripheral neuropathy would help advance cancer treatments (allowing for individualized precision treatments) and prevent the development of this dreaded complication.
| Shah, Arya; Hoffman, E Matthew; Mauermann, Michelle L et al. (2018) Incidence and disease burden of chemotherapy-induced peripheral neuropathy in a population-based cohort. J Neurol Neurosurg Psychiatry 89:636-641 |
