Metformin Combined With Chemotherapy for Pancreatic Cancer
Status:
Completed
Trial end date:
2014-04-01
Target enrollment:
Participant gender:
Summary
Pancreatic cancer patients have one of the worst prognoses among all cancer types with a 5
year survival rate of less than 5%. Despite significant changes during the last decade in our
molecular knowledge on this disease, the prognosis and management of pancreatic cancer have
remained unchanged. With the advances in molecular biology, newer biologic agents such as
erlotinib, are adding some benefit to the conventional cytotoxic agents. There is a growing
body of literature suggesting that type 2 diabetes mellitus (DM) may be associated with the
development of pancreatic cancer, but this association is complex. Because various DM
medications can affect directly the key factors mediating the association between DM and
pancreatic cancer, understanding the effect of anti-diabetic therapies on pancreatic cancer
is a critical step in fully characterizing the role of type 2 DM in the development of
pancreatic cancer. Indeed, two epidemiologic studies have found that diabetic patients
treated with metformin were less likely to develop cancer, but those treated with insulin
were more likely to die of various kinds cancer. Not only does metformin ameliorate
hyperglycemia and hyperinsulinemia, both of which are associated with the adverse impact of
DM on cancer, metformin also has direct metabolic effects through activation of adenosine
monophosphate-activated protein kinase (AMPK). AMPK regulates many metabolic enzymes and also
inhibits the mammalian target of rapamycin (mTOR) pathway via phosphorylation and
stabilization of the tumor suppressor gene TSC2. But there is an intensive cross-talk between
various pathways. Inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway, of which
mTOR is one of the effector proteins, for instance may result in escape via the
mitogen-activated protein kinase (MAPK) pathway and vice verse. Indeed, epidermal growth
factor receptor (EGFR) activation leads to activation of the MAPK pathway and the PI3K
pathway. Thus, since it is clear that blocking one pathway will not always be sufficient to
produce a response in the presence of other activated pathways, the best change of success
will be realized when using a combination of agents that inhibit separate pathways known to
be critical to the survival of the tumour. In line with these observations, combining a small
molecule against the EGFR and inhibition of the PI3K pathway by metformin might account for
potential candidates of the above combinatorial approach. Therefore, in this study, the
investigators want to determine the activity and safety of concurrent interruption of the
MAPK and PI3K pathways by the EGFR tyrosine kinase inhibitor erlotinib and metformin,
combined with gemcitabine in patients with metastatic pancreatic cancer.
Phase:
Phase 2
Details
Lead Sponsor:
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)