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A Study to Investigate the Safety and Efficacy of TRK-750 for the Treatment of Patients With CIPN (Chopin Study)

ABSTRACT: The primary objective of the study is: • to assess the safety and tolerability of multiple oral (twice daily [BID]) doses of TRK-750 in oxaliplatin-treated colorectal cancer patients with chemotherapy-induced peripheral neuropathy (CIPN). The secondary objectives of the study are: * to assess the efficacy of multiple oral (BID) doses of TRK-750 in reducing neuropathic symptoms, improving quality of life (QoL), and clinician-reported outcomes in oxaliplatin-treated colorectal cancer patients with CIPN. * to study the relationship between plasma concentrations of TRK-750 and safety and efficacy variables in oxaliplatin-treated colorectal cancer patients with CIPN. The exploratory objective of this study is: • to assess the efficacy of multiple oral (BID) doses of TRK-750 on pharmacodynamic (PD) biomarker(s) in blood, psychophysical, electrophysiological, and histological parameters of neuropathy in oxaliplatin-treated colorectal cancer patients with CIPN.

DISEASE(S): Chemotherapy Induced Peripheral Neuropathy,Chemotherapy-induced Peripheral Neuropathy,Peripheral Nervous System Diseases

PROVIDER: 2331108 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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αO-conotoxin GeXIVA[1,2] reduced neuropathic pain and changed gene expression in chronic oxaliplatin-induced neuropathy mice model

Project description:Chemotherapy induced peripheral neuropathy (CIPN) is a dose-limiting painful neuropathy that occurs commonly during cancer management, which often leads to the discontinuation of medication. Previous studies suggest that the α9α10 nicotinic acetylcholine receptor (nAChR) specific antagonist αO-conotoxin GeXIVA[1,2] is effective in CIPN models, however the related mechanisms remains unclear. Here we analyzed the preventive effect of GeXIVA[1,2] on neuropathic pain in the long-term oxaliplatin injection induced CIPN model. At the end of treatment, lumbar (L4-L6) spinal cord was extracted, and RNA-sequencing and bioinformatic analysis were performed to investigate the potential genes and pathways related to CIPN and GeXIVA[1,2]. GeXIVA[1,2] inhibited the development of mechanical allodynia induced by chronic oxaliplatin treatment. Repeated injections of GeXIVA[1,2] for 3 weeks have no effect on mice normal pain threshold or locomotor activity and anxiety-like behavior as evaluated in the open field test (OFT) and elevated plus maze (EPM). Our RNA-sequencing results identified 209 differentially expressed genes (DEGs) in CIPN model, simultaneously injection of GeXIVA[1,2] with oxaliplatin altered 53 of the identified DEGs. These reverted genes were significantly enriched in immune-related pathways represented by cytokine-cytokine receptor interaction pathway. Our findings suggest that GeXIVA[1,2] could be a potential therapeutic compound for chronic oxaliplatin induced CIPN management.

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Gene expression signatures of chemotherapy-induced neuropathy induced by cisplatin and oxaliplatin

Project description:Vincristine, oxaliplatin, and cisplatin are commonly prescribed chemotherapeutic agents for the treatment of several cancer types. However, a main side-effect is chemotherapy-induced peripheral neuropathy (CIPN), which may lead to decreased quality of life, changes in chemotherapeutic treatment or even treatment cessation. Although painful symptoms associated with CIPN are faithfully recapitulated by mouse models, there is limited knowledge of how these drugs affect the expression of genes in peripheral sensory neurons. The present study carried out a transcriptomic analysis of dorsal root ganglia isolated from mice treated with vincristine, oxaliplatin, and cisplatin with a view to gain insight into the comparative pathophysiological mechanisms of CIPN. RNA-Seq using 75-nucleotide single end runs revealed 368, 295 and 256 differential expressed genes (DEGs) induced by treatment with vincristine, oxaliplatin and cisplatin, respectively. Although there were many similarities in DEGs between chemotherapeutic agents, only 5 genes were dysregulated in all groups. Cell type enrichment analysis (CTEA) and gene set enrichment analysis (GSEA) showed predominant effects on genes associated with the immune system after treatment with vincristine, while oxaliplatin treatment affected mainly neuronal genes. Treatment with cisplatin resulted in a mixed inflammatory and neuropathic gene expression signature. Only ‘regulation of transport’ and ‘response to external stimuli’ were gene ontology terms shared between all treatments. These results provide insight into the recruitment of innate and adaptive immune responses to DRG tissue and indicate enhanced neuro-inflammatory processes following administration of vincristine, oxaliplatin, and cisplatin. These gene expression signatures may provide insight into novel drug targets for treatment of CIPN.

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Gene expression signatures of chemotherapy-induced neuropathy induced by vincristine

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2017-11-01 | E-MTAB-4656 | biostudies-arrayexpress

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| 2009841 | ecrin-mdr-crc

Preventive Treatment of Oxaliplatin Induced Peripheral Neuropathy in Metastatic Colorectal Cancer (POLAR-M)

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Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain

Project description:Neuroinflammation is a major component in the transition to and perpetuation of neuropathic pain states. Spinal neuroinflammation involves activation of TLR4, localized to enlarged, cholesterol-enriched lipid rafts, designated here as inflammarafts. Conditional deletion of cholesterol transporters ABCA1 and ABCG1 in microglia, leading to inflammaraft formation, induced tactile allodynia in naïve mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice, but AIBP failed to reverse allodynia in mice with ABCA1/ABCG1-deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia nor reversed CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia. These results suggest a cholesterol-driven mechanism of regulation of neuropathic pain by controlling TLR4 inflammarafts and gene expression program in microglia and blocking the perpetuation of neuroinflammation.

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