Mechanisms of chemotherapy neurotoxicity in iPSC-derived schwann cells and sensory neurons

Chemotherapy is widely used to treat various types of cancers but despite its therapeutic effects it often causes adverse side effects called chemotherapy-induced peripheral neuropathy (CIPN). Patients often experience pain, numbness, sensory and motor disturbances that negatively affect the daily living of cancer patients, cancer survivors and next of kin. The side effects are often doselimiting, but dose-reduction might risk the efficacy of the cancer treatment. The adverse side effects are primary located in the peripheral nervous system, which involves nerves that sense thermal- and pressure stimuli and other cell types e.g., Schwann cells. Paclitaxel, vincristine and bortezomib are some of the most common types of chemotherapy that cause CIPN.

The aim of this thesis was to better understand the cellular- and molecular mechanisms behind paclitaxel-, vincristine-, and bortezomib-induced peripheral neuropathy. Additionally, we wanted to assess the translational use of new biomarker within CIPN research. In the first study, we used an in vitro model utilizing induced pluripotent stem cell (iPSC)-derived Schwann cell precursors (iPSCderived SCP) and iPSC- derived-Schwann cells (iPSC-derived SC) to examine cellular- and transcriptional changes following exposure to paclitaxel or vincristine. Interestingly, paclitaxel downregulated lipid- and lipoprotein-related pathways in iPSC-derived SC that were connected to myelin- and repair-genes and high concentrations of vincristine seemed to dedifferentiate iPSC-derived SC.

The second study generated an overview of recent literature assessing neurofilament light chain (NFL) as a biomarker for chemotherapy-induced neurodegeneration in vitro, and CIPN in vivo and in patients. The literature mostly examined paclitaxel-induced peripheral neuropathy (PIPN) or paclitaxel-induced neurodegeneration. In the literature assessing NFL in vitro and in vivo, exposure to paclitaxel increased in NFL release. Also, vincristine treatment elevated NFL-release in rat serum. In patients, paclitaxel treatment resulted in 1.7-10-fold increase in NFL-levels while oxaliplatin and bortezomib caused 9- and 6-fold increase, respectively. Additionally, two studies predicted severe PIPN using NFL cut-off levels. This suggested that the use of NFL as biomarker for CIPN is very promising.

The third study gained insights into the use of NFL as a biomarker for bortezomib-induced neurodegeneration and bortezomib-induced peripheral neuropathy (BIPN). Bortezomib exposure caused concentration-dependent NFL release in iPSC-SN with large donor variation. Exposure to bortezomib also caused changes in nuclei morphology in iPSC-derived SC. Looking at serum NFL (sNFL)-levels in seven patients undergoing treatment with bortezomib, we found that sNFL-levels were generally moderately elevated after the first cycle of bortezomib, but more so after the second cycle. Multiple cycles of bortezomib resulted in greater variation in sNFL-levels between individuals. Larger prospective studies are needed to assess if sNFL can predict severe BIPN in patients.

This thesis adds to the understanding of the molecular and cellular mechanisms behind CIPN yet more in-depth research is needed. Future research should investigate if paclitaxel treatment affects myelination and e.g., nerve conduction in patients. Additionally, NFL needs to be prospectively, and clinically evaluated when used for CIPN caused by e.g., vincristine, cisplatin and oxaliplatin. Finally, standardized methods for reporting and measuring NFL are needed.