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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

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

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Gene expression signatures of chemotherapy-induced neuropathy induced by vincristine

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2022-03-24 | PXD028356 | Pride

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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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