Metformin, an inexpensive drug that has been prescribed for diabetes for decades, may also be useful in preventing or treating several types of cancer.
Since its 1995 approval by the U.S. Food and Drug Administration, metformin has become one of the most commonly prescribed medications for type 2 diabetes, but the drug has potential for other uses. Metformin is also being tested for treating prediabetes, polycystic ovary syndrome, and various cancers. If metformin’s efficacy in cancer treatment is proven, cancer patients may benefit not only medically but also financially—a month’s supply of the generic form of this oral medication costs less than $5 at many U.S. pharmacies.
Aung Naing, M.D., an associate professor in the Department of Investigational Cancer Therapeutics, is one of several researchers at The University of Texas MD Anderson Cancer Center who are currently leading studies of metformin. “This oldie for endocrinologists is the new kid on the block for oncologists,” he said.
Early results in many cancers
Dr. Naing cited two 2009 publications by MD Anderson researchers that alerted him to metformin’s potential anticancer activity. In the first study, a group in the Department of Breast Medical Oncology noticed that among 2,529 women with early-stage breast cancer, the pathological complete response rate after chemotherapy was higher (24%) in diabetic patients who had received metformin than in diabetic patients who had not received metformin (8%) and in nondiabetic patients (16%). In the second study, a group in the Department of Gastrointestinal Medical Oncology found that among 255 diabetic patients, the risk of developing pancreatic cancer was 62% lower in those who received metformin than in those who did not.
Since that time, researchers at MD Anderson have conducted several retrospective studies looking at outcomes of patients who had concurrent cancer and diabetes. In separate studies of patients who had prostate cancer, colorectal cancer, pancreatic cancer, triple-negative breast cancer, HER2-positive breast cancer, and multiple myeloma, the median overall survival durations were found to be longer in patients who had taken metformin than in those who had not.
Myriad molecular effects
At the translational research level, in vitro and in vivo studies have supported the use of metformin in several cancer types and, along with tumor specimen biomarker studies, have begun to elucidate the molecular mechanisms of metformin’s action.
Metformin seems to affect multiple key processes related to cell growth, proliferation, and survival. The drug’s effects on these processes stem from both metabolic and intracellular-signaling activity. First, metformin decreases the amount of glucose produced by the liver and reduces the bloodstream level and cellular uptake of insulin. In turn, the reduced insulin stimulation results in reduced activation of insulin receptors on cell membranes, triggering a cascade of intracellular molecular effects, such as the downregulation of the Ras/Raf/MEK/ ERK and PI3K/AKT/mTOR signaling pathways. One or both of these pathways are often activated in many types of cancer cells. In addition, metformin appears to upregulate AMP-activated protein kinase, a key molecule in glucose and insulin regulation and also an inhibitor of mTOR.
On the basis of retrospective and preclinical studies that indicated metformin’s potential as an anticancer agent, the drug is now being combined with traditional chemotherapy, radiation therapy, targeted therapy, and other cancer treatments in clinical trials. Metformin is also being studied in a single-agent cancer prevention trial. At the time of this writing, MD Anderson has six open clinical trials involving metformin, with several more under development.
Metformin in endometrial cancer
The link between diabetes and endometrial cancer makes metformin attractive as a potential treatment for the cancer. “Insulin resistance and diabetes are two of the main risk factors for endometrial cancer, and obesity—which is often seen with diabetes—increases the risk of endometrial cancer more than any other cancer,” said Pamela Soliman, M.D., M.P.H., an associate professor in the Department of Gynecologic Oncology and Reproductive Medicine.
Several molecular pathways affected by metformin come into play in endometrial cancer—in particular, the PI3K/ AKT/mTOR pathway. For this reason, Drs. Naing and Soliman are leading clinical trials combining metformin with another mTOR inhibitor. “If you block the same pathway with two mechanisms, you may get an additive effect,” said Dr. Soliman.
Dr. Soliman’s current phase II trial combines metformin with the mTOR inhibitor everolimus and the anti-estrogen agent letrozole for the treatment of advanced or recurrent endometrial cancer. This trial derived from an earlier trial in which patients received everolimus and letrozole. “A patient in that first trial developed diabetes, which is a side effect of mTOR inhibitors, and her primary care physician started her on metformin,” Dr. Soliman said. “The patient had had stable disease before metformin, but with metformin she started responding to the study drugs. Then I had another patient who was taking metformin and also started responding to the cancer treatment.” Dr. Soliman’s clinical observations prompted her to look at metformin in the lab; her group found in cell lines and mice that metformin decreased endometrial cancer cell growth. Next, the researchers looked at biomarkers in endometrial cancer patients’ baseline diagnostic biopsy specimens and post-metformin surgical specimens. Dr. Soliman reported on the molecular changes in these specimens at the 2014 American Society of Clinical Oncology Annual Meeting.
In addition to leading the everolimus/letrozole/metformin study, Dr. Soliman is the principal investigator at MD Anderson for a national trial for patients with stage III or IV endometrial cancer. One group of patients will be randomly assigned to receive standard-of-care chemotherapy (paclitaxel and carboplatin); the other group will receive those drugs plus metformin.
Dr. Naing’s combination treatment trial pairs metformin with the mTOR inhibitor temsirolimus. The trial’s first phase has enrolled patients with many types of advanced cancer, and the second phase will focus on patients with endometrial cancer. Dr. Naing has incorporated two innovative aspects into this trial.
First, Dr. Naing is using a dose-titration strategy that may ultimately allow higher doses of the drugs to be safely given than previous trials achieved. “Metformin is started at a low dose and gradually increased to a higher dose,” Dr. Naing said. “Then temsirolimus is started. In the first phase of the trial, this strategy reduced the side effects. And since one of the side effects of temsirolimus is hyperglycemia, which is treated with metformin, we are hitting two birds with one stone.”
A second innovation in the trial is that serial biopsy specimens will be collected from patients whose endometrial cancers have gene mutations that affect the PI3K/AKT/mTOR pathway. “A high frequency of mutations affecting this pathway is seen in endometrial cancer,” Dr. Naing said. Because metformin and temsirolimus both inhibit this pathway, he is interested to see whether changes will occur over time in the molecular profiles of the biopsied tissues.
Dr. Naing also hopes to learn whether the response to metformin is better in patients with certain mutations than in patients without the mutations. “We think it will be a signature trial for women with endometrial cancer,” Dr. Naing said.
Metformin in lung cancer
Two clinical trials combining metformin and radiation therapy for lung cancer will be opening soon.
Metformin’s effects on metabolism brought it to the attention of Heath Skinner, M.D., Ph.D., an assistant professor in the Department of Radiation Oncology. “One possible means of resistance to radiation is altered tumor metabolism,” said Dr. Skinner, whose group conducted in vitro and in vivo experiments suggesting that metabolically targeted drugs such as metformin would work as radiosensitizers. His next step was retrospective chart reviews looking at patients who were treated with radiation therapy and whether they were taking metformin. “In many of the populations we looked at—patients with head and neck, esophageal, and lung cancer—the patients taking metformin for their diabetes had a better outcome.”
On the basis of those results, Dr. Skinner is finalizing approval for a National Institutes of Health–funded clinical trial of stereotactic radiation therapy plus metformin for patients with inoperable stage IB non–small cell lung cancer. Patients will undergo a baseline positron emission tomography (PET) scan, receive metformin or placebo for 3 weeks, have another PET scan, and then continue the drug during radiation treatment; a third PET scan will be performed after 6 months. Dr. Skinner said, “We will be able to see whether metformin by itself affects the size of tumors seen on the PET scan and whether metformin plus radiation improves the outcome over radiation alone.”
Dr. Skinner is also a co–principal investigator on a national phase II trial sponsored by NRG Oncology, a nonprofit research organization. In this trial, which will soon be enrolling patients at MD Anderson, patients with locally advanced non–small cell lung cancer will be randomly selected to receive the standard-of-care treatment, chemoradiation, with or without metformin. “These two studies are the only ones I’m aware of that are combining metformin with radiation therapy,”
Dr. Skinner said.
Benefits and cautions
Metformin’s utility for cancer patients may extend beyond treatment and prevention. A group in MD Anderson’s Department of Symptom Research is studying whether the drug relieves chemotherapy-induced peripheral neuropathy. A recent preclinical study by the group showed that giving mice metformin along with cisplatin (compared with placebo and cisplatin) significantly reduced loss of paw sensitivity and protected peripheral-nerve endings. Despite metformin’s many potential benefits in cancer treatment and prevention, Dr. Naing cautioned that the drug’s use for cancer is still investigational. Robust clinical trials such as the ones under way are needed to ensure safety and efficacy.
Some precautions must be taken when prescribing metformin. Although very rare, lactic acidosis can occur with metformin use, particularly in patients with renal issues, so the drug is not recommended in patients with abnormal renal or hepatic function; nor is it prescribed in patients with heart failure. Also, metformin must be discontinued before the administration of an imaging contrast agent. Finally, metformin should be combined with other drugs with care.
These contraindications notwithstanding, metformin is widely used as an antidiabetic agent because its adverse effects are usually quite manageable; diarrhea, nausea, and vomiting are the most common. “The good thing about metformin,” Dr. Skinner said, “is it’s extraordinarily safe, it’s extraordinarily inexpensive, and it should be able to easily be integrated into cancer therapy.”
For more information, contact Dr. Aung Naing at 713-563-0181, Dr. Heath Skinner at 713-563-3508, or Dr. Pamela Soliman at 713-745-2352.
Hajjar J, Habra MA, Naing A. Metformin: an old drug with new potential. Exp Opin Invest Drugs. 2013;22:1511-1517.
OncoLog, November-December 2014, Volume 59, Issue 11-12