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Pharmacometabolomics reveals a role for histidine, phenylalanine, and threonine in the development of paclitaxel-induced peripheral neuropathy

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Abstract

Purpose

Approximately 25% of breast cancer patients experience treatment delays or discontinuation due to paclitaxel-induced peripheral neuropathy (PN). Currently, there are no predictive biomarkers of PN. Pharmacometabolomics is an informative tool for biomarker discovery of drug toxicity. We conducted a secondary whole blood pharmacometabolomics analysis to assess the association between pretreatment metabolome, early treatment-induced metabolic changes, and the development of PN.

Methods

Whole blood samples were collected pre-treatment (BL), just before the end of the first paclitaxel infusion (EOI), and 24 h after the first infusion (24H) from sixty patients with breast cancer receiving (80 mg/m2) weekly treatment. Neuropathy was assessed at BL and prior to each infusion using the sensory subscale (CIPN8) of the EORTC CIPN20 questionnaire. Blood metabolites were quantified from 1-D-1H-nuclear magnetic resonance spectra using Chenomx® software. Metabolite concentrations were normalized in preparation for Pearson correlation and one-way repeated measures ANOVA with multiple comparisons corrected by false discovery rate (FDR).

Results

Pretreatment histidine, phenylalanine, and threonine concentrations were inversely associated with maximum change in CIPN8 (ΔCIPN8) (p < 0.02; FDR ≤ 25%). Paclitaxel caused a significant change in concentrations of 2-hydroxybutyrate, 3-hydroxybutyrate, pyruvate, o-acetylcarnitine, and several amino acids from BL to EOI and/or 24H (p < 0.05; FDR ≤ 25%), although these changes were not associated with ΔCIPN8.

Conclusions

Whole blood metabolomics is a feasible approach to identify potential biomarker candidates of paclitaxel-induced PN. The findings suggest that pretreatment concentrations of histidine, phenylalanine, and threonine may be predictive of the severity of future PN and paclitaxel-induced metabolic changes may be related to disruption of energy homeostasis.

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Acknowledgements

We would like to thank Cora McHugh and Zyad Smiley at the University of Michigan College of Pharmacy Biochemical NMR Core for their technical and analytic support.

Funding

This work was supported through a Michigan Institute for Clinical and Health Research (MICHR) KL2 award to Dr. Daniel L. Hertz. Dr. Kathleen Stringer’s effort was supported, in part, by a Grant from the National Institute of General Medical Sciences (NIGMS R01 GM111400). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIGMS or the National Institutes of Health.

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Correspondence to Daniel L. Hertz.

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Dr. Daniel F. Hayes reports financial interest with Oncimmune LLC and Inbiomotion, serves as a consultant for Cepheid (no compensation), receives research grants from Merrimack Pharmaceuticals, Inc, Eli Lilly Company, Menarini/Silicon BioSystems, Puma Biotechnology, Inc, Pfizer, and Astra Zeneca, receives royalties from licensed technology from Janssen R&D, LLC, and holds three patents. The rest of the authors declare no conflict of interest.

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The study was approved by the University of Michigan IRBMed (HUM 00086253). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Sun, Y., Kim, J.H., Vangipuram, K. et al. Pharmacometabolomics reveals a role for histidine, phenylalanine, and threonine in the development of paclitaxel-induced peripheral neuropathy. Breast Cancer Res Treat 171, 657–666 (2018). https://doi.org/10.1007/s10549-018-4862-3

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