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Lipid profiling of pre-treatment plasma reveals biomarker candidates associated with response rates and hand–foot skin reactions in sorafenib-treated patients

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Abstract

Sorafenib is a multi-kinase inhibitor for treatment of advanced hepatocellular carcinoma (HCC). Beyond its clinical benefit against advanced HCC, the efficacy and safety of sorafenib chemotherapy are critical concerns. In this study, we addressed the lipid profiles associated with the efficacy and safety of sorafenib chemotherapy. Plasma samples from HCC patients before sorafenib chemotherapy (N = 44) were collected and subjected to lipidomic analysis. We measured the levels of 176 lipids belonging to 8 classes of phosphoglycerolipids, 2 classes of sphingolipids, 3 classes of neutral lipids, and 4 other classes of lipids. To characterize lipids associated with efficacy, we compared the responder group (N = 21; partial response and stable disease) with non-responder group (N = 22; progressive disease). To characterize lipids associated with hand–foot skin reaction (HFSR), we compared the susceptible group (N = 12; grade 2 and 3) with non-susceptible group (N = 32; grade 0 and 1). The levels of 8 lipids, including phosphatidylcholine (PC)[34:2], PC[34:3]a, PC[35:2], PC[36:4]a, PC[34:3e], acylcarnitine (Car)[18:0], cholesterol ester[20:2], and diacylglycerol (DG)[34:2], were significantly lower in the responder group, and 6 out of 8 these lipids contained FA(18:2). In addition, the levels of 7 lipids (Car[12:0], Car[18:0], Car[18:1], Car[20:1] and fatty acid amides (FAA[16:0], FAA[18:0], and FAA[18:1]b)) were significantly lower in the group susceptible to HFSR. Our comprehensive lipidomics study using samples from sorafenib-treated patients with HCC revealed that significant differences in the lipid profiles of pre-treatment plasma were associated with sorafenib efficacy and sorafenib-induced HFSR. Validation using another set of patient plasma samples and elucidating the molecular basis of these changes will lead to better treatment with sorafenib chemotherapy.

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Acknowledgements

The authors would like to thank Ms. Katsuko Toyoshima, Ms. Mai Kojima, and Mr. Ryota Iiji (National Institute of Health Sciences) for experimental assistance and Ms. Chie Sudo for secretarial assistance. This work was financially supported by the Japan Agency for Medical Research and Development (AMED) (Grant Numbers 17mk0101045j0303 and 17ak0101043j0603). This research was also supported by funding from Bayer Yakuhin, Ltd., under a research contract.

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Authors and Affiliations

  1. Division of Medical Safety Science, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan

    Kosuke Saito & Yoshiro Saito

  2. Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Masafumi Ikeda

  3. Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan

    Yasushi Kojima

  4. Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan

    Hiroko Hosoi & Shunsuke Kondo

  5. Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan

    Shunsuke Kondo

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  1. Kosuke Saito
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  2. Masafumi Ikeda
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  3. Yasushi Kojima
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  4. Hiroko Hosoi
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  5. Yoshiro Saito
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  6. Shunsuke Kondo
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Correspondence to Yoshiro Saito or Shunsuke Kondo.

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Conflict of interest

Shunsuke Kondo has received research funding from AstraZeneca, Eli Lilly Japan K.K., ASLAN, Pfizer, Takeda Yakuhin, Ltd., and Bayer Yakuhin, Ltd. None of the other authors have potential conflicts of interest to declare.

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Corresponding authors for lipidomics (Y. Saito) and clinical significance (S. Kondo).

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Saito, K., Ikeda, M., Kojima, Y. et al. Lipid profiling of pre-treatment plasma reveals biomarker candidates associated with response rates and hand–foot skin reactions in sorafenib-treated patients. Cancer Chemother Pharmacol 82, 677–684 (2018). https://doi.org/10.1007/s00280-018-3655-z

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