Repurposing an Old Drug for Cancer Control: What Does Metformin Bring to the Plate?
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston. Dr. Coleman reports no financial relationships relevant to this field of study.
This article originally appeared in the February 2013 issue of OB/GYN Clinical Alert.
Synopsis: Metformin use was associated with better disease-specific survival in women who developed ovarian cancer. The data support (preclinical observations of) the anticancer activity of metformin in several solid tumors and provide rationale for planned and ongoing clinical trials.
Source: Kumar S, et al. Metformin intake is associated with better survival in ovarian cancer: A case-control study. Cancer 2012; doi: 10.1002/cncr.27706. [Epub ahead of print].
In limited clinical trials, metformin has been shown to have anticancer activity. The objective of this study was to investigate whether patients taking metformin had better disease-specific survival compared to non-consumers. Since metformin use is generally reserved for control of diabetes, two control groups were used in the matched analysis: diabetic controls (those with ovarian cancer taking agents other than metformin for diabetic control) and non-diabetic controls (those patients with ovarian cancer that were not diabetic and did not receive metformin). Two cohorts of ovarian cancer patients were studied: those with ovarian cancer irrespective of histology (matched 1:2, case:control) and those with epithelial ovarian cancer (matched 1:3). Matching was based on age, stage, and residual disease.
In the all ovarian cancer analysis (72 cases and 143 controls), metformin cases had significantly better 5-year survival (73% vs 44%; P = 0.0002). In the epithelial ovarian cancer cohort (61 cases and 178 controls), metformin cases had significantly better 5-year survival (67% vs 47%; P = 0.007). On multivariate analysis, metformin remained independently associated with better survival (hazard ratio, 2.2; 95% confidence interval, 1.2-3.8; P = 0.007) after controlling for disease stage, grade, histology, chemotherapy, body mass index, and surgical cytoreduction. The authors conclude that metformin use was associated with improved disease-specific survival in patients with ovarian cancer and is worthy of further clinical testing in prospective clinical trials.
As our knowledge expands into the molecular underpinnings of disease initiation, invasion, metastasis, progression, and emergence of drug resistance, we are increasingly “rediscovering” the utility of existing drugs developed under other indications. There are many examples, but one of the most striking is the history of the development, retraction, and redevelopment of thalidomide, a drug initially developed in the 1950s as an antiemetic and a sedative.1 It was found to be particularly effective for hyperemesis gravidarum; as is well known, the agent was withdrawn after being found to be a teratogen. However, by serendipity, it was found to be active in relieving the symptoms of leprosy and gained approval in 1998 for this indication. It also was found to be a potent inhibitor of tumor necrosis factor alpha and angiogenesis.2 Under these actions, it found a home in the treatment of multiple myeloma, where it was granted accelerated approval by the FDA in 2006.3
Metformin’s effects on cancer biology are only beginning to be understood; there is clearly activation of an important mediator of PI3K pathway signaling, AMPK.4 This enzyme regulates the activity of the tuberous sclerosis proteins (TSC1/TSC2), which blocks the downstream targets of Akt, an important mediator of growth factor signaling, including VEGF, IGF1, and EGF. We have found in our own studies that metformin may add to the efficacy of other agents targeting this pathway, providing another therapeutic angle (Coleman R, unpublished). The association drawn from this paper must be interpreted with caution, however. As with all retrospective studies, the conclusions are hypothesis-generating and need to be formally tested in prospective clinical trials. Since the duration and time of administration of metformin was unknown, the impact of diabetes itself on the natural history of disease is unknown. Additionally, there are a number of confounders including the influence of insulin use on metformin users (and vice versa), the impact of undocumented prediagnosis use of metformin, and the limited ability to control for important therapeutic effects of medicines (IP chemotherapy, dose-dense chemotherapy, targeted agents in recurrence, etc). Therefore, causation cannot be assessed properly. However, the therapeutic window for this agent, its availability, and its cost should favorably usher a robust repurposing program.
1. Kumar V, Chhibber S. Thalidomide: An old drug with new action. J Chemother 2011;23:326-334.
2. Cook KM, Figg WD. Angiogenesis inhibitors: Current strategies and future prospects. CA Cancer J Clin 2010;60:222-243.
3. Latif T, et al. Thalidomide and its analogues in the treatment of multiple myeloma. Exp Hematol Oncol 2012;1:27.
4. Zakikhani M, et al. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006;66:10269-10273.