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Metformin in pancreatic cancer treatment: from clinical trials through basic research to biomarker quantification

  • Review – Clinical Oncology
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Abstract

Purpose

Three major chemotherapy strategies have emerged in the treatment of PDAC in the recent past: multiple drug combination, stroma depletion, and use of nanodrug therapy. Anti-diabetic metformin was shown to improve the outcome of a number of cancer types the first seminal report on an observational study published in 2005 and the first hospital-based case–control study on pancreatic cancer in 2009.

Methods

In this review paper, we confront the findings of a selected number of epidemiological studies and clinical trials on the use of metformin in pancreatic cancer treatment with basic knowledge and research. We particularly emphasize on the point that contradictory clinical results likely originate from heterogeneous study design due to a trial and error approach rather than an evidence-based and scientific approach. A non-rigorous selection of patients suffering from PDAC and often a poor understanding of the biological mechanism of metformin coupled with lack of scientific data has led to general statements on metformin positive or negative action, another aspect which we highlight in the review.

Results

We here present a few pathways which in our opinion are predominant for pancreatic cancer specifically: mitochondrial activity, AMPK activation, mTOR inhibition, and decreased IGF-1R and HIF-1α expression.

Conclusion

We stress on the need for a better stratification of patients and a more rigorous planning of clinical trials not only focusing on classical parameters but also on potential predictive biomarkers (AMPK, mTOR, HIF-1α, IGF-1R) and metformin dosage for positive outcome.

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Abbreviations

AKT:

Protein kinase B

AMPK:

5′ Adenosine monophosphate-activated protein kinase

APC:

Advanced pancreatic cancer

EGF:

Epidermal growth factor

ERK:

Extracellular signal-regulated kinase

HIF-1α:

Hypoxia-inducible factor-1α

HR:

Hormone receptor

IGF:

Insulin-like growth factor

IGF-1R:

Insulin-like growth factor 1 receptor

INSR:

Insulin receptor

mTOR:

Mammalian target of rapamycin

MEK:

Mitogen-activated protein kinase

MPC:

Metastatic pancreatic cancer

NFκB:

Nuclear factor kappa B

PI3K:

Phosphoinositide 3-kinase

PTEN:

Phosphatase and tensin homologue

SIAH:

Seven in abstensia homologue

STAT3:

Signal transducer and activator of transcription 3

T2DM:

Type 2 diabetes mellitus

References

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Acknowledgments

The authors are indebted to the Mauritius Research Council for funding drug delivery research.

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Correspondence to Dhanjay Jhurry.

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Conflict of interest

The authors declare that they have no conflict of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Bhaw-Luximon, A., Jhurry, D. Metformin in pancreatic cancer treatment: from clinical trials through basic research to biomarker quantification. J Cancer Res Clin Oncol 142, 2159–2171 (2016). https://doi.org/10.1007/s00432-016-2178-4

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  • DOI: https://doi.org/10.1007/s00432-016-2178-4

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