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

SIMPLE SUMMARY: Chemotherapy-induced peripheral neuropathy (CIPN) remains a clinical challenge with a considerable impact on the effective treatment of cancers and quality of life during and after concluding chemotherapy. Given the limited understanding of CIPN, there are no options for the treatment and prevention of CIPN. Decades of research with the unsuccessful translation of preclinical findings to clinical studies argue for the requirement of human model systems. This review focuses on the translational potential of human induced pluripotent stem cells (iPSCs) in CIPN research. We provide an overview of the current studies and discuss important aspects to improve the translation of in vitro findings. We identified distinct effects on the neurite network and cell viability upon exposure to different classes of chemotherapy. Our study revealed considerable variability between donors and between neurons of the central and peripheral nervous system. Translational success may be improved by including multiple iPSC donors with known clinical data and selecting clinically relevant concentrations. 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.