Investigating the Link Between Metabolism and Cancer

When Rachel Perry, PhD, assistant professor of medicine (endocrinology) and of cellular and molecular physiology, started her lab in 2018, she set out to understand how the tools used to study systemic metabolism could be applied in the context of cancer.

“We’re looking at how we can change the nutrients that we take in and the energy that we put out,” Perry explained. “For instance, we want to find out how can we alter exercise or other behavior to improve our body's metabolic or nutritional response to cancer.”

In an interview, Perry discusses the link between insulin and cancer, a surprising finding in her research, and the future of precision medicine for metabolism-related cancers.

Cancer cells divide quickly, and to grow, tumors require many nutrients. One of the major nutrients for tumors is glucose. Research has shown that insulin, a hormone produced by the pancreas, is key to regulating glucose uptake into tumors. Insulin tells various cells in the body to take up glucose in response to a meal to use for energy.

Individuals with obesity tend to be insulin resistant, meaning their cells don’t take up glucose in response to insulin. When that occurs, our bodies produce more insulin to allow us to overcome that insulin resistance. Insulin is both a growth factor and a metabolic factor in cells. Insulin tells tumor cells to take up glucose like it tells liver and muscle cells to take up glucose.

The problem is tumor cells do not become insulin resistant, whereas other cells in the body do. In an individual with obesity and insulin resistance, tumor cells continue to take up more glucose in response to insulin, but the other cells in the body do not. When insulin levels are high, and other cells aren't responding, more glucose is funneled into tumor cells.

Numerous studies have shown that low-carbohydrate diets and exercise can be beneficial.

We did a study in preclinical models in which we combined a drug called dichloroacetate, which can activate glucose oxidation, with immunotherapy. We thought that if you activate glucose metabolism, it could improve the response to immunotherapy. The drug didn't slow tumor growth, but it did reduce cancer-related fatigue.

We weren’t expecting to go in the direction of cancer-related fatigue, but my philosophy in the lab is we follow the science. Ninety percent of patients with cancer report substantial fatigue that impairs their quality of life and reduces the probability that they will complete cancer treatment. Currently, there are no effective medications for this debilitating condition. We hope that this drug can potentially help these patients.

There are 13 tumor types that the CDC has associated with obesity. But there are also people with a BMI under 30 who have metabolic dysfunction, and there are people with a BMI over 30 who do not have metabolic dysfunction. One key thing that we need to do is nuance our understanding of what obesity means and link tumor factors to metabolic dysfunction rather than BMI.

We are working to learn more about how systemic metabolism affects the immune response to cancer and the tumor's metabolic response to cancer. We hope to repurpose metabolic drugs used for diabetes or obesity to potentially improve cancer treatment.

We showed in a paper published a couple of years ago that in various breast cancer preclinical models, depending on the tumor genetics, different models respond better to insulin-lowering therapies. That research opens the possibility of developing precision medicine-type approaches to use metabolic therapy for cancer. That’s our goal moving on.

Yale School of Medicine’s Section of Endocrinology and Metabolism works to improve the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge, applying new information to patient care, and training the next generation of physicians and scientists to become leaders in the field. To learn more, visit Endocrinology and Metabolism.