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
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
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.
Print copy of the thesis is restricted to reference use in the Library.