City of Hope Scientist Explores Genomic Instability as the Key Link Between Diabetes and Cancer

Scientists have noticed that people with type 1 diabetes (T1D) and type 2 diabetes (T2D) are at higher risk for developing some types of cancer, but they’ve had a hard time explaining why. Now, they may have an answer: It appears that when blood sugar runs high, DNA is damaged more often and doesn’t get fixed, leading to cancer.

What’s more, some of the best new therapies for treating cancer, including immuno-oncology, can have the effect of triggering T1D, by charging up the immune system and allowing it attack insulin-producing beta cells in the pancreas.

Both the American Diabetes Association and some cancer advocacy groups have been raising awareness of the connection between diabetes and cancer in recent years. Cancer survival rates have been rising overall, but cancer rates that are related to diabetes and obesity have been increasing, and those with diabetes are more than twice as likely to develop cancer. People with diabetes are at higher risk of 13 types of cancer, including bladder, breast, liver, colorectal, endometrial, pancreatic, oral, and multiple myeloma.

John Termini, PhD, a professor in Molecular Medicine at City of Hope, a research and treatment center in Duarte, California, and his colleagues sought to come up with better answers than the guesses that had dominated thinking to this point. One was that people with T2D, who are often overweight, produce higher levels of adipokines that promote inflammation. “That’s probably part of it, but there hasn’t been a lot of solid evidence,” he said in a statement.

Instead, Termini and his team looked at modified DNA bases, known as adducts, in rodent models of diabetes. They discovered a DNA adduct called N2 (1-carboxyethyl)-2’-deoxyguanosine, or CEdG, which was seen more frequently in diabetic models than in normal cells or mice. In addition, the high glucose levels both (1) increased DNA strand breaks and (2) interfered with DNA repair, which meant that CEdG was not removed. This created the genomic instability that led to cancer.

Termini is presenting recent findings this week at the American Chemical Society Fall 2019 meeting in San Diego, including some possible treatment options. His results include:

• A clinical study that measured the levels of CEdG and a counterpart in RNA in people with T2D. Termini showed that those with T2D had higher levels of CEdG and the RNA measure, called CEG, than people without diabetes.
• Identification of 2 proteins that show less activity in diabetes and may explain why adducts are not repaired. HIF1α activates genes in the repair process, and mTORC1 controls HIF1α.

“We found that if we stabilize HIF1α in a high-glucose environment, we increase DNA repair and reduce DNA damage,” Termini’s statement said. “And mTORC1 actually controls HIF1α, so if you stimulate mTORC1, you stimulate HIF1α.”

Fortunately, he continued, treatments that stimulate these proteins already exist—including metformin, which is already widely used and inexpensive. (Interestingly, metformin’s anticancer qualities have already been observed and are being tested in clinical trials through the National Cancer Institute, including a trial combining the immunotherapy nivolumab with metformin.)

Termini said researchers will examine whether these drugs reduce cancer risk in animal models with diabetes; if this is successful, the regimen will be tested in humans.

“Metformin helps lower blood glucose and stimulates DNA repair,” he said. “We’re looking to test metformin in combination with drugs that specifically stabilize HIF1α or enhance mTORC1 signaling in diabetic animal models.”

In the short-term, the best bet is for people with diabetes to closely manage their blood glucose, which Termini acknowledges is easier said than done. “It’s extremely difficult for most people to maintain glycemic control,” he said.

Reference

Termini JS. TOXI 4: hyperglycemia induced DNA damage and inhibition of DNA repair: potential mechanistic link between diabetes and increased cancer risk. Presented at: American Chemical Society National Meeting; August 25, 2019; San Diego, CA. plan.core-apps.com/acs_sd2019/abstract/d5901b87-9d3d-4061-abc5-e96df83ef123. Accessed August 26, 2019.