Heeschen(ChemotherapyAdvisor) – Metformin was found to target human pancreatic cancer stem cells in preclinical mouse models, according to study results presented June 19 at the American Association for Cancer Research’s Pancreatic Cancer: Progress and Challenges conference, Lake Tahoe, NV.
“These data provide a strong experimental basis for further evaluating the combination of metformin and chemotherapeutic drugs to eventually improve the poor prognosis of patients with pancreatic cancer,” noted Christopher Heeschen, MD, PhD, of the Spanish National Cancer Research Centre in Madrid, Spain.
In this study, low-dose metformin selectively targeted freshly isolated human pancreatic cancer stem cells. “Specifically, metformin pretreated sphere-derived cancer stem cells showed strong activation of AMPK and loss of expression of pluripotency-associated genes and cancer stem cell-associated surface markers,” they found.
“Consecutively, the ability of pretreated cancer stem cells to expand clonally in vitro and in vivo was virtually abrogated, while noncancer stem cells remained mostly unaffected by metformin treatment.” p53 wild-type cancer stem cells were found to be resistant to the effects of metformin, while induction of energetic crisis resulting in enhanced apoptosis was restricted to p53-deficient cancer stem cells, they found.
Combining metformin with gemcitabine, the standard chemotherapeutic agent for pancreatic cancer, efficiently erased both cancer stem cells and non-cancer stem cells and, in primary tissue xenograft mouse models, this combination effectively reduced tumor burden and prevented relapse vs either drug alone, they found.
“Intriguingly, in all tumors treated with metformin to date, relapse of disease was efficiently prevented and there were no noticeable adverse effects,” Dr. Heeschen said. He believes that testing metformin in pancreatic cancer is ready for clinical trials.
The team is currently awaiting results of a study that tested metformin as a maintenance treatment in patients with advanced pancreatic cancer. Although the rationale for this study was based on retrospective data, Dr. Heeschen said, given these new results, he hopes that this treatment strategy would be highly efficacious.
“Pending the results of this study, an important aspect for the future will be to investigate if all patients respond to metformin or whether some patients, due to distinct genetic alterations, may not respond to this metabolic reprogramming,” he said.