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Metabolomic prediction of treatment outcome in pancreatic ductal adenocarcinoma patients receiving gemcitabine

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Abstract

Purpose

Resistance to gemcitabine remains a key challenge in the treatment of pancreatic ductal adenocarcinoma (PDAC), necessitating the constant search for effective strategies for a priori prediction of clinical outcome. While the existing studies focused on aberration of drug disposition genes and proteins as molecular predictors of gemcitabine treatment outcomes, the metabolic aberration associated with chemoresistance in clinical PDAC has been neglected. This exploratory study investigated the potential role of tissue metabolomics in characterizing the clinical treatment outcome of gemcitabine therapy.

Methods

Surgically resected tumors from PDAC patients who underwent gemcitabine-based adjuvant chemotherapy (n = 25) were subjected to metabotyping using gas chromatography/time-of-flight mass spectrometry (GC/TOFMS).

Results

A partial least-squares discriminant analysis (PLS-DA) model clearly distinguished patients who had favorable survival [overall survival (OS) > 24 months] from those who exhibited poorer survival (OS < 16 months) (Q 2 = 0.302). Receiver-operating characteristic analysis demonstrated the robustness of the PLS-DA model with an area under the curve of 1. PLS-DA revealed 19 marker metabolites (e.g., lactic acid, proline, and pyroglutamate) that shed insights into the chemoresistance of gemcitabine in PDAC. Particularly, tissue levels of lactic acid complemented transcript expression levels of human equilibrative nucleoside transporter 1 in distinguishing patients according to their overall survival.

Conclusion

This work established proof-of-principle for GC/TOFMS-based global metabotyping of PDAC and laid the foundation for future discovery of metabolic biomarkers predictive of gemcitabine resistance in PDAC chemotherapy.

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Acknowledgements

This work was supported by the Singapore General Hospital Research Grant (SRG#09/2015) provided to LCP and the Singapore Ministry of Education Tier 1 Grant (R-148-000-204-112) provided to ECYC. The authors would like to thank Dr. Chng Kern Rei for providing statistical support.

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Authors and Affiliations

  1. Department of Clinical Translational Research, Singapore General Hospital, Singapore, Singapore

    Lee Cheng Phua

  2. Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore

    Shixu Goh & Eric Chun Yong Chan

  3. Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore

    David Wai Meng Tai

  4. Department of Pathology, Singapore General Hospital, Singapore, Singapore

    Wei Qiang Leow, Syed Muhammad Fahmy Alkaff & Tony Kiat Hon Lim

  5. Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore

    Chung Yip Chan & Juinn Huar Kam

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  1. Lee Cheng Phua
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Correspondence to Lee Cheng Phua, Tony Kiat Hon Lim or Eric Chun Yong Chan.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Phua, L.C., Goh, S., Tai, D.W.M. et al. Metabolomic prediction of treatment outcome in pancreatic ductal adenocarcinoma patients receiving gemcitabine. Cancer Chemother Pharmacol 81, 277–289 (2018). https://doi.org/10.1007/s00280-017-3475-6

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