Diabetes Drug Emerges as Potential Therapy in Multiple Cancers

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

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.

Metformin entered the picture because of its recognized stimulatory effect on AMP-activated protein kinase (AMPK) signaling. Boosting AMPK signaling has an inhibitory effect on mTORC1, providing a rationale for metformin in HNSCC, NIH researcher J. Silvio Gutkind, PhD, and coauthors reported in Cancer Prevention Research.

In tests involving HNSCC cells, the investigators showed that metformin inhibited mTORC1 activity by AMPK-dependent and independent mechanisms. Using a mouse model of oralspecific carcinogenesis (a precursor to HNSCC), they found that metformin inhibited mTORC1 in the basal proliferating epithelial layer of premalignant lesions.

“Remarkably, metformin prevented the development of HNSCC by reducing significantly the size and number of carcinogen-induced oral tumoral lesions and by preventing their spontaneous conversion to squamous-cell carcinoma,” Gutkind, chief of Oral and Pharyngeal Cancer at the National Institute of Dental and Craniofacial Research, and coauthors wrote in their conclusion. “Collectively, our data underscore the potential clinical benefits of using metformin as a targeted chemopreventive agent in the control of HNSCC development and progression.”

Lastly, biochemist Geoffrey D. Girnun, PhD, and colleagues at the University of Maryland in Baltimore reported that metformin blocked tumor development in a mouse model of liver cancer.⁴ Epidemiologic evidence had shown that patients with diabetes have an increased risk of hepatocellular carcinoma (HCC), which is reduced in patients treated with metformin, according to the researchers.

In contrast to the study by Gutkind et al, Girnun and colleagues found that metformin did not increase AMPK activation, but instead decreased expression of lipogenic enzymes and lipogenesis, known contributors to liver cancer.

In metformin-resistant states, restoration of lipogenic gene expression by ectopic expression of transcription factor SREBP1c restored metforminmediated growth inhibition.

“This mechanism of action suggests that metformin may also be useful for patients with other disorders associated with HCC in which increased lipid synthesis is observed,” the authors wrote in conclusion. “As a whole, these studies show that metformin prevents HCC and that metformin should be evaluated as a preventive agent for HCC in readily identifiable at-risk patients.”

References

1. Sadeghi N, Abbruzzese JL, Yeung SC, Hassan M, Li D. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res. 2012;18(10):2905-2912.
2. Martin MJ, Hayward R, Viros A, Marais R. Metformin accelerates the growth of BRAFV600E -driven melanoma by upregulating VEGF-A. Cancer Discov. 2012;2(4):344-355.
3. Vitale-Cross L, Molinolo AA, Martin D, et al. Metformin prevents the development of oral squamous cell carcinomas from carcinogeninduced premalignant lesions. Cancer Prev Res (Phila). 2012;5(4):562-573.
4. Bhalla K, Hwang BJ, Dewi RE, et al. Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev Res (Phila). 2012;5(4):544-552.