Cargando…

Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts

There is currently tremendous interest in developing anti-cancer therapeutics targeting cell signaling pathways important for both cancer cell metabolism and growth. Several epidemiological studies have shown that diabetic patients taking metformin have a decreased incidence of pancreatic cancer. Th...

Descripción completa

Detalles Bibliográficos
Autores principales: Lipner, Matthew B., Marayati, Raoud, Deng, Yangmei, Wang, Xianxi, Raftery, Laura, O’Neil, Bert H., Yeh, Jen Jen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711922/
https://www.ncbi.nlm.nih.gov/pubmed/26760500
http://dx.doi.org/10.1371/journal.pone.0147113
_version_ 1782409983955042304
author Lipner, Matthew B.
Marayati, Raoud
Deng, Yangmei
Wang, Xianxi
Raftery, Laura
O’Neil, Bert H.
Yeh, Jen Jen
author_facet Lipner, Matthew B.
Marayati, Raoud
Deng, Yangmei
Wang, Xianxi
Raftery, Laura
O’Neil, Bert H.
Yeh, Jen Jen
author_sort Lipner, Matthew B.
collection PubMed
description There is currently tremendous interest in developing anti-cancer therapeutics targeting cell signaling pathways important for both cancer cell metabolism and growth. Several epidemiological studies have shown that diabetic patients taking metformin have a decreased incidence of pancreatic cancer. This has prompted efforts to evaluate metformin, a drug with negligible toxicity, as a therapeutic modality in pancreatic cancer. Preclinical studies in cell line xenografts and one study in patient-derived xenograft (PDX) models were promising, while recently published clinical trials showed no benefit to adding metformin to combination therapy regimens for locally advanced and metastatic pancreatic cancer. PDX models in which patient tumors are directly engrafted into immunocompromised mice have been shown to be excellent preclinical models for biomarker discovery and therapeutic development. We evaluated the response of four PDX tumor lines to metformin treatment and found that all four of our PDX lines were resistant to metformin. We found that the mechanisms of resistance may occur through lack of sustained activation of adenosine monophosphate-activated protein kinase (AMPK) or downstream reactivation of the mammalian target of rapamycin (mTOR). Moreover, combined treatment with metformin and mTOR inhibitors failed to improve responses in cell lines, which further indicates that metformin alone or in combination with mTOR inhibitors will be ineffective in patients, and that resistance to metformin may occur through multiple pathways. Further studies are required to better understand these mechanisms of resistance and inform potential combination therapies with metformin and existing or novel therapeutics.
format Online
Article
Text
id pubmed-4711922
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-47119222016-01-26 Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts Lipner, Matthew B. Marayati, Raoud Deng, Yangmei Wang, Xianxi Raftery, Laura O’Neil, Bert H. Yeh, Jen Jen PLoS One Research Article There is currently tremendous interest in developing anti-cancer therapeutics targeting cell signaling pathways important for both cancer cell metabolism and growth. Several epidemiological studies have shown that diabetic patients taking metformin have a decreased incidence of pancreatic cancer. This has prompted efforts to evaluate metformin, a drug with negligible toxicity, as a therapeutic modality in pancreatic cancer. Preclinical studies in cell line xenografts and one study in patient-derived xenograft (PDX) models were promising, while recently published clinical trials showed no benefit to adding metformin to combination therapy regimens for locally advanced and metastatic pancreatic cancer. PDX models in which patient tumors are directly engrafted into immunocompromised mice have been shown to be excellent preclinical models for biomarker discovery and therapeutic development. We evaluated the response of four PDX tumor lines to metformin treatment and found that all four of our PDX lines were resistant to metformin. We found that the mechanisms of resistance may occur through lack of sustained activation of adenosine monophosphate-activated protein kinase (AMPK) or downstream reactivation of the mammalian target of rapamycin (mTOR). Moreover, combined treatment with metformin and mTOR inhibitors failed to improve responses in cell lines, which further indicates that metformin alone or in combination with mTOR inhibitors will be ineffective in patients, and that resistance to metformin may occur through multiple pathways. Further studies are required to better understand these mechanisms of resistance and inform potential combination therapies with metformin and existing or novel therapeutics. Public Library of Science 2016-01-13 /pmc/articles/PMC4711922/ /pubmed/26760500 http://dx.doi.org/10.1371/journal.pone.0147113 Text en © 2016 Lipner et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Lipner, Matthew B.
Marayati, Raoud
Deng, Yangmei
Wang, Xianxi
Raftery, Laura
O’Neil, Bert H.
Yeh, Jen Jen
Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts
title Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts
title_full Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts
title_fullStr Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts
title_full_unstemmed Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts
title_short Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts
title_sort metformin treatment does not inhibit growth of pancreatic cancer patient-derived xenografts
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711922/
https://www.ncbi.nlm.nih.gov/pubmed/26760500
http://dx.doi.org/10.1371/journal.pone.0147113
work_keys_str_mv AT lipnermatthewb metformintreatmentdoesnotinhibitgrowthofpancreaticcancerpatientderivedxenografts
AT marayatiraoud metformintreatmentdoesnotinhibitgrowthofpancreaticcancerpatientderivedxenografts
AT dengyangmei metformintreatmentdoesnotinhibitgrowthofpancreaticcancerpatientderivedxenografts
AT wangxianxi metformintreatmentdoesnotinhibitgrowthofpancreaticcancerpatientderivedxenografts
AT rafterylaura metformintreatmentdoesnotinhibitgrowthofpancreaticcancerpatientderivedxenografts
AT oneilberth metformintreatmentdoesnotinhibitgrowthofpancreaticcancerpatientderivedxenografts
AT yehjenjen metformintreatmentdoesnotinhibitgrowthofpancreaticcancerpatientderivedxenografts