Chemotherapy‐induced peripheral neuropathy: Identifying the research gaps and associated changes to clinical trial design

Germain, Diane C. St.; O’Mara, Ann; Robinson, Jennifer L.; Torres, Andrea; Minasian, Lori M.

doi:10.1002/cncr.33108

Cited by 14 publications

(11 citation statements)

References 140 publications

(292 reference statements)

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“…In such situations, specific mechanisms or receptors are hard to assess. Within the published mechanistic studies, only a small fraction focused on functional neuronal properties [69].…”

Section: Discussionmentioning

confidence: 99%

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Generation of human nociceptor-enriched sensory neurons for the study of pain-related dysfunctions

Holzer

Karreman

Suciu

et al. 2022

Preprint

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In vitro models of the peripheral nervous system would benefit from further refinements to better support studies on neuropathies. In particular, the assessment of pain-related signals is still difficult in human cell cultures. Here, we harnessed induced pluripotent stem cells (iPSCs) to generate peripheral sensory neurons enriched in nociceptors. The objective was to generate a culture system with signaling endpoints suitable for pharmacological and toxicological studies. Neurons generated by conventional differentiation protocols expressed moderate levels of P2X3 purinergic receptors and only low levels of TRPV1 capsaicin receptors, when maturation time was kept to the upper practically-useful limit of 6 weeks. As alternative approach, we generated cells with an inducible NGN1 transgene. Ectopic expression of this transcription factor during a defined time window of differentiation resulted in highly-enriched nociceptor cultures, as determined by functional (P2X3 and TRPV1 receptors) and immunocytochemical phenotyping, complemented by extensive transcriptome profiling. Single cell recordings of Ca2+-indicator fluorescence from >9,000 cells were used to establish the "fraction of reactive cells" in a stimulated population as experimental endpoint, that appeared robust, transparent and quantifiable. To provide an example of application to biomedical studies, functional consequences of prolonged exposure to the chemotherapeutic drug oxaliplatin were examined at non-cytotoxic concentrations. We found (i) neuronal (allodynia-like) hypersensitivity to otherwise non-activating mechanical stimulation that could be blocked by modulators of voltage-gated sodium channels; (ii) hyper-responsiveness to TRPV1 receptor stimulation. These findings and several other measured functional alterations indicate that the model is suitable for pharmacological and toxicological studies related to peripheral neuropathies.

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“…In such situations, specific mechanisms or receptors are hard to assess. Within the published mechanistic studies, only a small fraction focused on functional neuronal properties [69].…”

Section: Discussionmentioning

confidence: 99%

“…In such situations, specific mechanisms or receptors are hard to assess. Within the published mechanistic studies, only a small fraction focused on functional neuronal properties [69]. Morphology-based test methods are more wide-spread and better-established, but they may miss signaling changes [28].…”

Section: Discussionmentioning

confidence: 99%

Generation of human nociceptor-enriched sensory neurons for the study of pain-related dysfunctions

Holzer

Karreman

Suciu

et al. 2022

Preprint

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“… 12 Unfortunately, to date, there are no effective regimens to successfully tackle paclitaxel-induced peripheral neuropathy. 13 Moreover, single target drugs have previously been applied to treat PIPN, but to no avail. Accordingly, it is imperative to advance the search for novel therapeutic targets to reduce the plight of PIPN.…”

Section: Introductionmentioning

confidence: 99%

Shaoyao Gancao Decoction Ameliorates Paclitaxel-Induced Peripheral Neuropathy via Suppressing TRPV1 and TLR4 Signaling Expression in Rats

Chen

Wang

et al. 2022

DDDT

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“…Despite the extensive research effort focused on understanding mechanisms involved in the development of CIPN, the translation of this mechanistic understanding into rationally-designed, clinical intervention studies remains problematic [ 7 ]. According to a study conducted by investigators at the National Cancer Institute, based on databases covering the period January 2011 to May 2019, only 3 of 35 clinical trials that investigated agents or devices to treat CIPN incorporated a mechanistic rationale to support the choice of the intervention.…”

Section: Introductionmentioning

confidence: 99%

Emerging Pharmacological and Non-Pharmacological Therapeutics for Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy

Lustberg

2021

Cancers

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Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event of several first-line chemotherapeutic agents, including platinum compounds, taxanes, vinca alkaloids, thalidomide, and bortezomib, which negatively affects the quality of life and clinical outcome. Given the dearth of effective established agents for preventing or treating CIPN, and the increasing number of cancer survivors, there is an urgent need for the identification and development of new, effective intervention strategies that can prevent or mitigate this debilitating side effect. Prior failures in the development of effective interventions have been due, at least in part, to a lack of mechanistic understanding of CIPN and problems in translating this mechanistic understanding into testable hypotheses in rationally-designed clinical trials. Recent progress has been made, however, in the pathogenesis of CIPN and has provided new targets and pathways for the development of emerging therapeutics that can be explored clinically to improve the management of this debilitating toxicity. This review focuses on the emerging therapeutics for the prevention and treatment of CIPN, including pharmacological and non-pharmacological strategies, and calls for fostering collaboration between basic and clinical researchers to improve the development of effective strategies.

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Chemotherapy‐induced peripheral neuropathy: Identifying the research gaps and associated changes to clinical trial design

Cited by 14 publications

References 140 publications

Generation of human nociceptor-enriched sensory neurons for the study of pain-related dysfunctions

Generation of human nociceptor-enriched sensory neurons for the study of pain-related dysfunctions

Shaoyao Gancao Decoction Ameliorates Paclitaxel-Induced Peripheral Neuropathy via Suppressing TRPV1 and TLR4 Signaling Expression in Rats

Emerging Pharmacological and Non-Pharmacological Therapeutics for Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy

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