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Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).

ABSTRACT: Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients.

SUBMITTER: Chhibber A

PROVIDER: S-EPMC4111770 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).

Chhibber A A Mefford J J Stahl E A EA Pendergrass S A SA Baldwin R M RM Owzar K K Li M M Winer E P EP Hudis C A CA Zembutsu H H Kubo M M Nakamura Y Y McLeod H L HL Ratain M J MJ Shulman L N LN Ritchie M D MD Plenge R M RM Witte J S JS Kroetz D L DL

The pharmacogenomics journal 20140211 4

Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genoty ...[more]

PMID: 24513692

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Project description:Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of morbidity and the main cause of dose reductions and discontinuations in cancer treatment. Preclinical evidence indicates that activation of the Wallerian-like degeneration pathway driven by sterile alpha and TIR motif containing 1 (SARM1) is responsible for axonopathy in CIPN. SARM1 is the central driver of an evolutionarily conserved programme of axonal degeneration downstream of chemical, inflammatory, mechanical or metabolic insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathies of the peripheral and central nervous systems. Small molecule SARM1 inhibitors have the potential to prevent axonal degeneration in peripheral and central axonopathies and to provide a transformational disease-modifying treatment for these disorders. Using a biochemical assay for SARM1 NADase we identified a novel series of potent and selective irreversible isothiazole inhibitors of SARM1 enzymatic activity that protected rodent and human axons in vitro. In sciatic nerve axotomy, we observed that these irreversible SARM1 inhibitors decreased a rise in nerve cADPR and plasma neurofilament light chain released from injured sciatic nerves in vivo. In a mouse paclitaxel model of CIPN we determined that Sarm1 knockout mice prevented loss of axonal function, assessed by sensory nerve action potential amplitudes of the tail nerve, in a gene-dosage-dependent manner. In that CIPN model, the irreversible SARM1 inhibitors prevented loss of intraepidermal nerve fibres induced by paclitaxel and provided partial protection of axonal function assessed by sensory nerve action potential amplitude and mechanical allodynia.

Dataset Information

Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).

Publications

Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).

Similar Datasets

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