Diabetes Drug Emerges as Potential Therapy in Multiple Cancers

Published: Monday, Jul 02, 2012
Dr. Donghui Li

Donghui Li, PhD

Four studies released during the 2012 AACR Annual Meeting reflected the growing interest in—and the volume of evidence for—using the diabetes drug metformin as a potential cancer therapy.

In one of the studies, patients with coexistent pancreatic cancer and diabetes had a 50% higher 2-year survival if they had received metformin.1 The researchers’ retrospective chart review showed that 117 patients treated with metformin had a 2-year survival of 30.1% compared with 15.4% for 185 patients who did not receive the drug. The metformin subgroup had a median overall survival of 15.2 months versus 11.1 months for the other patients, resulting in a 32% reduction in the mortality hazard, as reported online in Clinical Cancer Research.

“Our study suggests that metformin may improve the overall survival rates of patients with diabetes and nonmetastatic pancreatic cancer independent of other known prognostic factors,” Donghui Li, PhD, professor of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, and coauthors wrote in conclusion. “The antitumor effect of metformin may translate into clinical benefit in the form of improved response to chemotherapy and prolonged survival.”

Li and colleagues presented data from the only clinical study among the four. The researchers retrospectively identified all patients with pancreatic cancer and precancer diagnosis of diabetes from 2000 to 2009. They then separated the patients according to whether or not they had received metformin.

The patients had a median age of 64 at diagnosis and a mean body mass index of approximately 27. Baseline characteristics differed in only two respects: Patients not treated with metformin had a significantly higher rate of insulin use (48.1% vs 24.8%; P <.001), and more patients in the metformin group had cancer that involved the tail of the pancreas (20.5% vs 11.9%; P = .042).

The patients had a median follow-up of 11.4 months, and 1-year survival for the study population was 53%, including all disease stages. One year after diagnosis, 64% of the metformin group remained alive, compared with 46% of the patients who were not treated with the drug (P = .002). Both the 2-year and median overall survival showed a significant advantage for the metformin group (P = .004, P = .009).

Patients with metastatic cancer had no better survival with metformin than without. Exclusion of patients with metastatic disease resulted in an even larger reduction in the mortality hazard in the metformin group (hazard ratio = 0.53; P = 0.001).

Another study involving patient-derived melanoma cells and preclinical models showed that adding metformin to the angiogenesis inhibitor bevacizumab (Avastin) unexpectedly boosted growth suppression by 64% compared with 34% with bevacizumab alone.2 The observation was unexpected because metformin alone accelerated tumor growth in a melanoma model, George Marais, PhD, and coauthors reported in Cancer Discovery.

Metformin Molecular Model

Metformin Molecular Model

The observation also prompted a caveat about metformin. “Our results suggest that care should be taken when prescribing metformin to patients with BRAF-mutant melanoma, as it could potentially worsen their disease,” said Marais, director of the Paterson Institute for Cancer Research in Manchester, England, in a statement from the AACR meeting.

The caveat came from the mixed signals produced by a series of laboratory studies. Investigators evaluated the effects of metformin in BRAF-mutant and NRAS-mutant melanoma cells. They found that metformin inhibited growth of NRAS-mutant cells by 68% to 100%, but had no effect on BRAF-mutant cells. More than half of all melanomas have BRAF mutations. Marais and colleagues subsequently found that metformin also upregulates vascular endothelial growth factor (VEGF)-A.

The key to the disparate findings proved to be ribosomal S6 kinase (RSK), which is activated in BRAF-mutant melanoma. In contrast, NRAS-mutant melanoma has low RSK activity. Bevacizumab blocked VEGF-A and depleted or inhibited RSK in BRAF-mutant melanoma cells, making the cells sensitive to the antitumor effects of metformin.

Evidence from another preclinical study suggested that metformin might also have a role in treating or preventing head and neck squamous cell carcinoma (HNSCC).3 The key target in the study was mammalian target of rapamycin complex 1 (mTORC1), which was recently identified as a signaling pathway in HNSCC.

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