At a recent virtual symposium — “Diabetes and Cancer Interface: Connecting the Dots” — City of Hope gynecologic cancer expert Lorna Rodríguez-Rodriguez, M.D., Ph.D., issued a call to arms of sorts for new collaborations investigating the links between type 2 diabetes and ovarian cancer.
Rodríguez-Rodriguez is vice chair for faculty development in the Department of Surgery and professor of gynecologic oncology. In her presentation, she reviewed data from studies around the world and outlined some important unanswered questions. She believes City of Hope might just be the place to find answers.
“At City of Hope, people having such a depth of knowledge in one entity or the other, it makes logical sense that if you put both groups together, you’d have the best alignment of planets you could imagine,” she said.
Type 2 diabetes has been shown to increase the risk for a number of cancers, including tumors of the breast and endometrium. It also makes those diseases deadlier for the patients who must face them. In fact, connections between the two were first noted more than 100 years ago.
What’s more, the results of heightened blood sugar cause molecular changes that make it easier for tumors to grow, whether it’s through oxidation and inflammation or help in forming new blood vessels to feed the fast-growing cells.
Some alterations from diabetes that promote cancer may be permanent, lasting even after blood sugar is under control, due to a phenomenon known as “metabolic memory.” The mechanisms undergirding metabolic memory are beginning to be understood thanks to research led by Rama Natarajan, Ph.D., City of Hope’s National Business Products Industry Professor in Diabetes Research.
While the association between type 2 diabetes and endometrial cancer is well-established, evidence is thinner for connections to ovarian cancer. However, recent research analyzing data from 19 studies covering almost 30 years indicates that diabetes does indeed increase the risk for ovarian cancer.
There are underlying common elements between type 2 diabetes and ovarian cancer that provide some hints about how the former disease might contribute to the latter:
- obesity as a contributing factor
- increased insulin
- chronic inflammation
- increased signaling in biochemical pathways that regulate metabolism
- increases in steroid hormones in the ovaries
One biochemical pathway that is boosted in type 2 diabetes, STAT3, also has been found to create a cascade that helps ovarian cancer spread, according to research by Hua Yu, Ph.D., City of Hope’s Billy and Audrey L. Wilder Professor in Tumor Immunotherapy.
Clinical data indicates that increases in ovarian hormones caused by type 2 diabetes result in chronic inflammation, a condition that can set the stage for tumors to form and progress. A number of biochemical effects of diabetes activate signaling pathways that promote ovarian cancer, and side effects of diabetes can increase estrogen — a sex hormone that recent lab research implicates as playing a role in ovarian cancer.
“This is prime time for us to be having these discussions, because we have never looked at ovarian cancer through the endocrine microscope,” Rodriguez-Rodriguez told her colleagues.
One Promising Direction
Rodriguez-Rodriguez pointed to metformin, a widely used medication for type 2 diabetes that is already approved by the Food and Drug Administration, as a therapy that merits more research for its potential to address ovarian cancer — or perhaps even prevent it. It is already employed to treat polycystic ovary syndrome, which some studies have linked to endometrial and ovarian cancers.
Although the exact chemistry behind how metformin works is not fully understood, there is early evidence for its effectiveness against ovarian cancer.
Lab research has identified multiple biochemical mechanisms by which metformin seems to act against ovarian cancer. A 2012 retrospective investigation of clinical data published showed that, among women who have both type 2 diabetes and ovarian cancer, the drug reduces the risk of cancer recurrence and increases likelihood of survival over the course of 10 years.
Over the years, small case-control studies have demonstrated a range of benefits for ovarian cancer patients. A clinical trial from earlier this year showed metformin, in combination with certain standards of care, increases overall survival. Those scientists also found molecular signs that the medicine was having an antitumor effect.
According to Rodriguez-Rodriguez, metformin by itself may not be the answer for all ovarian cancer patients, but may be promising as part of an overall treatment regimen, particularly for patients with type 2 diabetes.
“It’s a simple drug that does so many things, and it’s pretty clear that some of them have to do with cancer,” Rodriguez-Rodriguez said. “We need research to understand how it works so that we can design better clinical trials.”