(Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: An open-label, randomized phase II trial

Clinical Cancer Research

Volumn 22, Issue 5, 2016, Pages 1076-1085

  Reni, Michele ^a   Dugnani, Erica ^a   Cereda, Stefano ^a   Belli, Carmen ^a   Balzano, Gianpaolo ^a   Nicoletti, Roberto ^a   Liberati, Daniela ^a   Pasquale, Valentina ^a   Scavini, Marina ^a   Maggiora, Paola ^a   Sordi, Valeria ^a   Lampasona, Vito ^a   Ceraulo, Domenica ^a   Di Terlizzi, Gaetano ^a   Doglioni, Claudio ^a,b   Falconi, Massimo ^a,b   Piemonti, Lorenzo ^a  

^a SAN RAFFAELE HOSPITAL   (Italy)

^b VITA SALUTE SAN RAFFAELE UNIVERSITY   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ADIPONECTIN; BILIRUBIN; CAPECITABINE; CISPLATIN; COMPLEMENT FACTOR D; CREATININE; EPIRUBICIN; GASTRIC INHIBITORY POLYPEPTIDE; GEMCITABINE; GHRELIN; GLUCAGON; GLUCAGON LIKE PEPTIDE 1; GLUCOSE; INSULIN; INTERLEUKIN 6; LEPTIN; METFORMIN; NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; PLASMINOGEN ACTIVATOR INHIBITOR 1; RESISTIN; TUMOR MARKER; TUMOR NECROSIS FACTOR ALPHA; ANTINEOPLASTIC AGENT; DEOXYCYTIDINE;

ADD ON THERAPY; ADULT; AGED; ARTICLE; CONTROLLED STUDY; DISEASE FREE SURVIVAL; DRUG EFFICACY; DRUG SAFETY; FEMALE; GENE EXPRESSION; HUMAN; INTENTION TO TREAT ANALYSIS; MAJOR CLINICAL STUDY; MALE; MULTIPLE CYCLE TREATMENT; OPEN STUDY; OVERALL SURVIVAL; PANCREAS CANCER; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; RANDOMIZED CONTROLLED TRIAL; SINGLE NUCLEOTIDE POLYMORPHISM; TREATMENT OUTCOME; TREATMENT RESPONSE; UNSPECIFIED SIDE EFFECT; ANALOGS AND DERIVATIVES; CLINICAL TRIAL; KAPLAN MEIER METHOD; MIDDLE AGED; PANCREATIC NEOPLASMS; PATHOLOGY;

ADULT; AGED; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CAPECITABINE; CISPLATIN; DEOXYCYTIDINE; DISEASE-FREE SURVIVAL; EPIRUBICIN; FEMALE; HUMANS; KAPLAN-MEIER ESTIMATE; MALE; METFORMIN; MIDDLE AGED; PANCREATIC NEOPLASMS; TREATMENT OUTCOME;

EID: 84962300475     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-15-1722     Document Type: Article

References (50)

1. Stern RJ, Murphy EJ. Metformin as initial oral therapy in type 2 diabetes. JAMA 2015;313:2484-5.
2. Baron B, Wang Y, Maehara S, Maehara Y, Kuramitsu Y, Nakamura K. Resistance to gemcitabine in the pancreatic cancer cell lineKLM1-R reversed by metformin action. Anticancer Res 2015;35:1941-9.
3. Wang LW, Li ZS, Zou DW, Jin ZD, Gao J, Xu GM. Metformin induces apoptosis of pancreatic cancer cells. World J Gastroenterol 2008;14: 7192-8.
4. Kisfalvi K,Moro A, Sinnett-Smith J, Eibl G, Rozengurt E. Metformin inhibits the growth of human pancreatic cancer xenografts. Pancreas 2013;42: 781-5.
5. Cifarelli V, Lashinger LM, Devlin KL, Dunlap SM, Huang J, Kaaks R, et al. Metformin and rapamycin reduce pancreatic cancer growth in obese prediabetic mice by distinct MicroRNA-regulated mechanisms. Diabetes 2015;64:1632-42.
6. Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding XZ, et al. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 2001;120:1263-70.
7. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008;8:915-28.
8. Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res 2009;69: 6539-45.
9. Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 2010;120:2355-69.
10. Cusi K, Consoli A,DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1996;81:4059-67.
11. Karnevi E, Said K, Andersson R, Rosendahl AH. Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells. BMC Cancer 2013; 13:235.
12. Pollak MN. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov 2012;2:778-90.
13. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005;310:1642-6.
14. Rozengurt E, Sinnett-Smith J, Kisfalvi K. Crosstalk between insulin/insulinlike growth factor-1 receptors and G protein-coupled receptor signaling systems: a novel target for the antidiabetic drug metformin in pancreatic cancer. Clin Cancer Res 2010;16:2505-11.
15. Nair V, Sreevalsan S, Basha R, Abdelrahim M, Abudayyeh A, Rodrigues Hoffman A, et al. Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors. J Biol Chem 2014;289:27692-701.
16. Sinnett-Smith J, Kisfalvi K, Kui R, Rozengurt E. Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: dependence on glucose concentration and role of AMPK. Biochem Biophys Res Commun 2013;430:352-7.
17. Kalender A, Selvaraj A, Kim SY, Gulati P, Brule S, Viollet B, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010;11:390-401.
18. Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, et al. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res 2011;71: 4366-72.
19. Nair V, Pathi S, Jutooru I, Sreevalsan S, Basha R, Abdelrahim M, et al. Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors. Carcinogenesis 2013;34:2870-9.
20. Nakamura M, Ogo A, Yamura M, Yamaguchi Y, Nakashima H. Metformin suppresses sonic hedgehog expression in pancreatic cancer cells. Anticancer Res 2014;34:1765-9.
21. Tanaka R, Tomosugi M, Horinaka M, Sowa Y, Sakai T. Metformin causes G1-phase arrest via down-regulation of MiR-221 and enhances TRAIL Sensitivity through DR5 Up-regulation in pancreatic cancer cells. PLoS One 2015;10:e0125779.
22. Gou S, Cui P, Li X, Shi P, Liu T, Wang C. Low concentrations of metformin selectively inhibit CD133(+) cell proliferation in pancreatic cancer and have anticancer action. PLoS One 2013;8:e63969.
23. Lonardo E, Cioffi M, Sancho P, Sanchez-Ripoll Y, Trabulo SM, Dorado J, et al. Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PLoS One 2013;8:e76518.
24. Tan XL, Bhattacharyya KK, Dutta SK, Bamlet WR, Rabe KG, Wang E, et al. Metformin suppresses pancreatic tumor growth with inhibition of NFkappaB/ STAT3 inflammatory signaling. Pancreas. 2015;44:636-47.
25. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52:1766-77.
26. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005;330:1304-5.
27. Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals.BMCCancer. 2011;11:20.
28. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009;137: 482-8.
29. Zhang P, Li H, Tan X, Chen L, Wang S. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiol 2013;37:207-18.
30. Choi Y, Kim TY,Oh DY, Lee KH, Han SW, Im SA, et al. The impact of diabetes mellitus and metformin treatment on survival of patients with advanced pancreatic cancer undergoing chemotherapy. Cancer Res Treat 2015.
31. Sadeghi N, Abbruzzese JL, Yeung SC, Hassan M, Li D. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res 2012;18:2905-12.
32. Suissa S, Azoulay L. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care 2012;35:2665-73.
33. Walker EJ, Ko AH, Holly EA, Bracci PM. Metformin use among type 2 diabetics and risk of pancreatic cancer in a clinic-based case-control study. Int J Cancer 2015;136:E646-53.
34. Bodmer M, Becker C, Meier C, Jick SS, Meier CR. Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis.AmJGastroenterol 2012;107:620-6.
35. Morden NE, Liu SK, Smith J, Mackenzie TA, Skinner J, Korc M. Further exploration of the relationship between insulin glargine and incident cancer: a retrospective cohort study of older Medicare patients. Diabetes Care 2011;34:1965-71.
36. van Staa TP, Patel D, Gallagher AM, de Bruin ML. Glucose-lowering agents and the patterns of risk for cancer: a study with the General Practice Research Database and secondary care data. Diabetologia 2012;55:654-65.
37. Singh S, Singh PP, Singh AG, Murad MH, McWilliams RR, Chari ST. Antidiabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis. Am J Gastroenterol 2013;108:510-9; quiz 20.
38. Hwang AL, Haynes K, Hwang WT, Yang YX. Metformin and survival in pancreatic cancer: a retrospective cohort study. Pancreas 2013;42:1054-9.
39. Nakai Y, Isayama H, Sasaki T, Mizuno S, Sasahira N, Kogure H, et al. Clinical outcomes of chemotherapy for diabetic and nondiabetic patients with pancreatic cancer: better prognosis with statin use in diabetic patients. Pancreas 2013;42:202-8.
40. Home PD, Kahn SE, Jones NP, Noronha D, Beck-Nielsen H, Viberti G. Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (a diabetes outcome progression trial) and RECORD (rosiglitazone evaluated for cardiovascular outcomes and regulation of glycaemia in diabetes) clinical trials. Diabetologia 2010;53: 1838-45.
41. Reni M, Cereda S, Rognone A, Belli C, Ghidini M, Longoni S, et al. A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen). Cancer Chemother Pharmacol 2012;69:115-23.
42. Zhou K, Bellenguez C, Spencer CC, Bennett AJ, Coleman RL, Tavendale R, et al. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 2011;43:117-20.
43. Reni M, Cereda S, Balzano G, Passoni P, Rognone A, Fugazza C, et al. Carbohydrate antigen 19-9 change during chemotherapy for advanced pancreatic adenocarcinoma. Cancer 2009;115:2630-9.
44. Kordes S, Pollak MN, Zwinderman AH, Mathot RA, Weterman MJ, Beeker A, et al. Metformin in patients with advanced pancreatic cancer: a doubleblind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 2015;16:839-47.
45. Okon IS, Zou MH. Mitochondrial ROS and cancer drug resistance: Implications for therapy. Pharmacol Res 2015;100:170-4.
46. Cheng G, Lanza-Jacoby S. Metformin decreases growth of pancreatic cancer cells by decreasing reactive oxygen species: Role of NOX4. Biochem Biophys Res Commun 2015;465:41-6.
47. Chandel N. Four key questions about metformin and cancer. BMC Biol 2014;12:85.
48. Huang B, Cheng X, Wang D, Peng M, Xue Z, Da Y, et al. Adiponectin promotes pancreatic cancer progression by inhibiting apoptosis via the activation of AMPK/Sirt1/PGC-1alpha signaling. Oncotarget 2014;5: 4732-45.
49. Birsoy K, Possemato R, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B, et al. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 2014;508:108-12.
50. Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014;510:542-6.