Study Explores Mechanism Linking Statin to Reduced Tumor Size in Endometrial Cancer

For years, scientists have noticed a link between statins and lower cancer rates, but the mechanism is not well-studied as a cancer therapy. An abstract presented Monday at the Society of Gynecologic Oncology’s 2018 Annual Meeting on Women’s Cancer, taking place in New Orleans, Louisiana, explored the metabolic process of how statins reduced tumor size in genetically engineered mice.

Lindsay West, MD, a fellow in gynecologic oncology at the University of North Carolina (UNC) at Chapel Hill, said her team’s experiments show that not only does simvastatin fight tumors in endometrial cancer, the effect is greatest when subjects are obese. This has important implications, given that half of all endometrial cancers rates can be attributed to obesity, and US obesity rates are rising.

As West noted, most of the epidemiological evidence on statins comes from cardiovascular studies, including that for endometrial cancer, which has a particularly high association with obesity. The National Cancer Institute reports statins may have a protective effect against colorectal cancer, and a large, 14-year study reported last year at the European Society of Cardiology found statin use was associated with lower rates of breast cancer and subsequent mortality.

The Experiment

Researchers used 2 groups of study mice: 1 group was fed a low-fat diet (10% calories from fat, the lean group) and the other a high-fat diet (60% calories derived from fat, the obese group) to mimic diet-induced obesity, starting at 3 weeks of age. At 6 weeks, the mice were treated to induce invasive endometrial cancer. The mice were then given simvastatin or placebo once tumors appeared (3 mg/kg per day for 4 weeks). Researchers measured tumor size and body weight, and lipid and metabolic behavior to evaluate both the effects of simvastatin as well as the effects of obesity on the tumors.

Results

West explained that simvastatin use did not affect overall body weight. The obese mice were larger than the lean mice (30 g compared with 25 g, P <.0001), consistent with those treated with simvastatin (28 g v. 24 g P <.02). But the statin use did shrink tumor size by 46% in the obese mice and by 30% in the lean mice (P <.05). Simvastatin appeared to have significant metabolic effects that interfered with tumor growth, with greater effects in the obese mice.

“Striking differences were seen especially as it pertained to lipid biosynthesis and storage in the obese tumor,” West said.

Statins work by inhibiting HMG-CoA reductase, which reduces cholesterol biosynthesis and regulates lipid metabolism. Without simvastatin, lipid storage in the obese mice fueled the aggressive tumor growth. West reviewed the metabolic results to explain how the simvastatin had different effects on the lean and obese mice. In lean mice, the drug impaired beta oxidation, with fatty acids diverted to lipid storage. But when the obese mice took simvastatin, beta oxidation was already impaired, and the drug furthered impaired oxidation.

“However, in obese tumors, lipid storage was already at maximum capacity,” she said, and the drug blocked the free fatty acids from going to lipid storage. Because free fatty acids could not go to beta oxidation and could not be stored, they accumulated in the cell, West said, “becoming lipotoxic,” and creating the enhanced effect against the tumors in these mice.

As a result, she said, researchers at the UNC Chapel Hill are in the earliest stages of investigating this concept with atorvastatin.

In an interview with The American Journal of Managed Care^®, West said this concept is not designed to show whether statins could be used in primary prevention against cancer, but the studies could eventually lead to statins being given to patients routinely once endometrial cancer is diagnosed. With their low cost and well-established track record in health plans, “statins could be an attractive therapy in obesity-driven cancers.”