Improving the understanding and prediction of chemotherapy-induced peripheral neuropathy

Chemotherapy remains a cornerstone in the treatment of multiple cancers. While therapeutically effective, chemotherapy frequently causes adverse effects that reduce the quality of life among cancer patients and survivors. Specific types of chemotherapy damage the peripheral nervous system which causes a variety of symptoms, including pain, numbness, tingling, and impaired sensation of stimuli, such as touch and temperature. This condition is also known as chemotherapy-induced peripheral neuropathy (CIPN).


Despite decades of research, there are no effective therapies or approaches available to prevent or treat this feared adverse effect. The clinical manifestations of CIPN are variable with respect to clinical presentation, onset, progression, and regression. Due to heterogeneity in clinical phenotypes, CIPN is challenging to diagnose and predict using the current subjective methods. The heterogeneity among patients with CIPN might be explained by different underlying pathophysiological mechanisms.


Fibroblasts from a skin biopsy can be used to generate human induced pluripotent stem cells (iPSCs) which can subsequently be differentiated into almost any cell type of the human body. We used iPSCs from two healthy donors to develop sensory neurons that constitute the cell type primarily affected in patients with CIPN.


In this thesis, we aimed to identify important aspects for clinical translation using iPSCderived models. Additionally, we wanted to investigate a translational biomarker of this adverse effect and provide a deeper understanding of the underlying pathophysiological mechanisms.


In the first study, we summarized the current literature regarding the use of iPSC-derived models to study CIPN. Although the number of studies was limited, we found that iPSC-derived models can replicate the heterogeneity of CIPN and identify different cellular phenotypes. Translational success of iPSC-derived models can potentially be improved by i) including iPSC donors with known clinical background e.g., asymptomatic CIPN, or severe CIPN, and ii) using chemotherapy concentrations known to be achievable in patients and account for plasma protein binding, and iii) developing co-culture or 3D human model systems.


We performed a translational study in collaboration with the Lillebaelt University Hospital of Southern Denmark to investigate if neurofilament light chain (NFL) was a useful biomarker of paclitaxel-induced peripheral neuropathy (PIPN). Our results showed that NFL is released from iPSC-derived sensory neurons following axonal damage by paclitaxel. We also measured the biomarker in patients with ovarian cancer before and during paclitaxel/carboplatin chemotherapy and found that patients present with varying degrees of increases in NFL levels after first cycle. This can be used to distinguish between patients at high risk of severe PIPN and paclitaxel dose modifications versus patients who tolerate the chemotherapy well.


Finally, we wanted to examine if different cellular phenotypes could be observed between paclitaxel and vincristine, and whether efflux transporters played a role in CIPN. We found that paclitaxel and vincristine caused distinct morphological but similar transcriptional alterations of iPSC-derived sensory neurons. By inhibition and induction of efflux transporters, we show that they can exacerbate or alleviate paclitaxel- and vincristine-induced neurotoxicity


While this thesis adds new pieces to the puzzle of CIPN, there are many more missing pieces to be found in future studies. The novel biomarker NFL needs clinical evaluation for the various chemotherapeutic agents associated with CIPN, including (but not limited to) paclitaxel, vincristine, oxaliplatin, and bortezomib. This will determine if NFL can be used as a general biomarker of CIPN and if NFL is suitable for implementation into routine oncology practice. Furthermore, we demonstrated in all three studies that iPSCderived sensory neurons have tremendous translational value for CIPN research. We revealed that induction of the efflux transporter P-glycoprotein is a potential strategy for protecting sensory neurons from chemotherapy-induced neurotoxicity. Future studies can utilize hypothesis-free approaches, such as single-cell sequencing and CRISPR interference screen, in iPSC-derived sensory neurons to reveal novel therapeutic targets. This might accelerate the development of effective therapies to reduce the significant burden of CIPN among patients living with and beyond cancer.