Bridging the Translational Gap in Chemotherapy-Induced Peripheral Neuropathy with iPSC-Based Modeling

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially serious adverse effect of a wide range of chemotherapeutics. The lack of understanding of the molecular mechanisms underlying CIPN limits the efficacy of chemotherapy and development of therapeutics for treatment and prevention of CIPN. Human induced pluripotent stem cells (iPSCs) have become an important tool to generate the cell types associated with CIPN symptoms in cancer patients. We reviewed the literature for iPSC-derived models that assessed neurotoxicity among chemotherapeutics associated with CIPN. Furthermore, we discuss the gaps in our current knowledge and provide guidance for selecting clinically relevant concentrations of chemotherapy for in vitro studies. Studies in iPSC-derived neurons revealed differential sensitivity towards mechanistically diverse chemotherapeutics associated with CIPN. Additionally, the sensitivity to chemotherapy was determined by donor background and whether the neurons had a central or peripheral nervous system identity. We propose to utilize clinically relevant concentrations that reflect the free, unbound fraction of chemotherapeutics in plasma in future studies. In conclusion, iPSC-derived sensory neurons are a valuable model to assess CIPN; however, studies in Schwann cells and motor neurons are warranted. The inclusion of multiple iPSC donors and concentrations of chemotherapy known to be achievable in patients can potentially improve translational success.