Study questions anti-cancer mechanisms of drug tested in clinical trials

January 13, 2014

CINCINNATI - The diabetes drug metformin is also being tested in numerous clinical trials for treating different cancers, and several studies point to its apparent activation of a molecular regulator of cell metabolism called AMPK to suppress tumor growth.

But new research appearing the week of Jan. 13 in Proceedings of the National Academy of Sciences (PNAS) suggests that activation of AMPK may actually fuel cancer growth. Researchers from Cincinnati Children's Hospital Medical Center who led the study also recommend that clinicians testing metformin for cancer treatment consider a careful re-evaluation of their clinical data.

The researchers report on extensive laboratory tests that conclude metformin does stop cancer, although not by activating AMPK. Instead, in tests involving glioma brain cancer cells, the authors found that metformin inhibits a different molecule called mammalian target of rapamycin (mTOR) that has been linked to many other cancers.

In the body, metformin also suppresses the actions of insulin and insulin-like growth factors - two molecules that support cancer growth - and also likely independent of AMPK, according to Biplab Dasgupta, PhD, principal investigator and a researcher in the Division of Hematology/Oncology at Cincinnati Children's.

"Our findings do not suggest that clinical trials using metformin should be stopped. Metformin appears to be a very useful drug, but the drug's mechanism of cancer suppression is not clear," Dr. Dasgupta said. "However, our findings unveil a potential role for AMPK as a tumor growth supporter, not a suppressor, in the type of cancer that we study. This is why clinicians using metformin in clinical trials should use caution during data interpretation."

Dasgupta and his research colleagues decided to tackle the question of metformin's anti-cancer properties because some studies point to AMPK as a tumor suppressor, while others have suggested it can promote tumor growth. Ultimately, an accurate understanding of AMPK's role - and how a drug like metformin does stop cancer - will likely be important to continued improvement of targeted cancer therapies, he said.

AMPK is a metabolic enzyme that acts as a key sensor of energy levels in cells. It controls a number of metabolic pathways that allow cells to regulate their energy usage and survival under physiological stress. Cancer cells modify their metabolism to maintain their growth and survival in the stressful environment of the tumor.

To determine how AMPK and metformin react in the context of cancer, the researchers conducted tests using glioblastoma, a highly lethal brain cancer with no cure. Their experiments involved laboratory cell cultures of human glioblastoma cells and glioblastoma tumors transplanted in mice to obtain results in a living organism.

Compared to normal human and mouse tissue, the researchers found that AMPK was highly active in human and mouse glioblastoma cells. This led them to question whether the anti-cancer properties of metformin were independent of AMPK, and instead directed to other molecular pathways.

The researchers then treated human glioblastoma cells with metformin and conducted a series of genetic tests to determine the molecular pathways it uses to stop the cancer growth. Those tests showed clearly that metformin directly inhibited the mTOR pathway (and the cancer) by promoting the interaction of two upstream molecules that stop the pathway's function.

To further verify that AMPK activation by metformin is not involved in stopping the growth of cancer, the researchers also treated the glioblastoma cells with a more specific AMPK activating compound called A769662 that directly binds to AMPK. The treatment did not kill glioblastoma cells, according to the authors.

Dasgupta and his colleagues are continuing their research by testing direct genetic inhibition of AMPK to see how it impacts human glioblastoma cells. Although that research still has to be completed and the results verified, he said preliminary indications are that blocking AMPK appears to kill a significant number of the glioblastoma cells.
-end-
The current study involved a collaboration of several scientists from Cincinnati Children's, including first co-author Xiaona Liu, MD, and Rishi Raj Chhipa, PhD, Division of Oncology. Other collaborating institutions included: the University of Cincinnati College of Medicine, the Mayfield Clinic, the Mayo Clinic, Katholieke Universiteit in Leuven, Belgium, Antwerp University Hospital in Belgium, the Inserm Institut Cochin and the Universite Paris Decartes, both in Paris, France.

Funding support for the study came from CancerFreeKids, the Smith-Brinker Golf Foundation, a Cincinnati Children's Trustee Scholar Grant and the National Institutes of Health (1RO1NS075291-01A1).

About Cincinnati Children's:

Cincinnati Children's Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in U.S. News and World Report's 2013 Best Children's Hospitals ranking. It is ranked #1 for cancer and in the top 10 for nine of 10 pediatric specialties. Cincinnati Children's, a non-profit organization, is one of the top three recipients of pediatric research grants from the National Institutes of Health, and a research and teaching affiliate of the University of Cincinnati College of Medicine. The medical center is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. Additional information can be found at http://www.cincinnatichildrens.org. Connect on the Cincinnati Children's blog, via Facebook and on Twitter.

Cincinnati Children's Hospital Medical Center

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.