Preclinical Study Reveals Potential Role for GLP Agonists in Endometrial Cancer

Using a glucagon-like peptide-1 (GLP-1) agonist such as semaglutide (Ozempic) in the management of endometrial cancer may impact cell viability through the proliferation pathway, according to Danielle Krause, MD, who added that the addition of GLP-1 receptor (GLP-1R) agonist therapy to progesterone did not negatively impact the therapeutic effect of progesterone in an obesity-associated mouse model.¹

“We wanted to [examine] what these [GLP-1] receptors are doing and if they have increased expression in patients with pathology like endometrial cancer or its precursor, endometrial hyperplasia,” she said in an interview with OncLive^®.

Findings from the study presented by Krause at the SGO 2024 Winter Meeting also demonstrated that the GLP-1R protein and mRNA expression are increased in endometrial cancer. Notably, improved survival was observed when a GLP agonist was added to progesterone vs other groups in the rodent study.

Currently, GLP-1R agonist therapy with tirzepatide (Mounjaro) is approved by the FDA for the treatment of patients with type 2 diabetes.²

In the interview, Krause, a gynecologic oncology fellow at the OU Health Stephenson Cancer Center in Oklahoma City, Oklahoma, detailed implications of the study’s findings and future directions for research examining GLP agonists in endometrial cancer.

OncLive: What was the rationale for examining GLP-1R agonist therapy in endometrial cancer?

Krause: With the obesity epidemic we’re also seeing rising numbers of endometrial cancer. This makes sense because the most common type of endometrial cancer is driven by obesity, particularly estrogen excess. There are a lot of newer and exciting medications focused on weight loss and the management of some of the comorbidities of obesity. We also wanted to see if some of these common medications like semaglutide and [other] GLP-1 receptor agonists could also be used in the endometrial cancer arena, or at least in congruence with some of the medications that we’re using already.

[In our study] we looked at different endometrial cancers in vitro and [evaluated] the effect that GLP-1R agonists would have in terms of growth of the cells, proliferation, [and] apoptosis. Furthermore, we took these cells, injected them into mice, and then administered GLP-1R agonist therapy to the mice, looking at the effect [the agents] were having on tumor growth as well as things like body weight and obesity markers.

What are some of the main findings from the study?

When looking at the in vitro studies, we see [results that are] congruent and consistent with some preliminary studies. We know that GLP-1 receptors exist on a variety of tissues in the body, [which is confirmed by] the FDA approval for their use in weight loss and diabetes. These receptors are very active on [certain] organs such as the liver and pancreas, but we are also finding that these receptors are [present] on the endometrium as well.

First, we looked at the expression of these receptors and compared [that] with [expression in] benign endometrium. We are seeing increased expression [of GLP-1R] both at the mRNA and protein level in endometrial cancer. Furthermore, we’re seeing higher expression as the cancer advances which signals that this may be something that we can act on in patients with endometrial cancer. That was one big finding—these [receptors] are present and active, so [they can] potentially be acted on.

Then we treated the endometrial cancer cells with GLP-1R agonists and found that they were affecting the ways the cells were growing. We weren’t seeing obvious evidence of cell death, but we were seeing decreased proliferation which was exciting. We use progesterone therapy in a lot of these patients, especially in those who aren’t surgical candidates, and whenever you’re adding a new drug to a well-known and studied cancer treatment, you always want to make sure that it’s not eliminating the effects of the drug that’s already well studied. [One of the most exciting and reassuring findings is that] when we used GLP-1R agonists in combination with progesterone therapy, we were still seeing the well-known effects of progesterone. [Adding GLP-1 agonists] didn’t negate those effects and wasn’t causing anything worse to happen. That was also proven in our animal studies.

Progesterone is known to have effects on endometrial cancer—it suppresses [tumor] growth and causes cell death—and we continued to see that. With the addition of a GLP-1R agonist, we were seeing the same effects on the cancer. However, the mice were not gaining as much weight as they were in the progesterone-only group which is a known adverse effect of progesterone therapy. That was exciting and something that will be looked at in future studies.

Did any of these findings come as a surprise to you?

With a lot of the preliminary work that was already done, [the results] were not a surprise, but they reassured us that this is an avenue we can continue down. I have a feeling that patients are [receiving] GLP-1R agonists and progesterone therapy in combination already, so having the science to back it up is reassuring and something that we’ll use going forward. With the effects of GLP-1R agonist [monotherapy], this could also be an exciting new avenue to look at different treatments for patients who can’t have surgery.

Could GLP-1 receptor agonist therapy complement the use of immunotherapy?

Immunotherapy is a hot topic in endometrial cancer and has [demonstrated] some amazing results. When we look at the molecular profiling of endometrial cancer, we’re seeing the biggest benefit with immunotherapy in patients who are mismatch repair gene deficient. [Conversely], patients that have obesity-driven endometrial cancer typically have copy number–low or no specific molecular [disease] and that’s usually where we’re seeing obesity driving the endometrial cancer. Currently, I don’t see an obvious additive effect of adding the 2 combination therapies because these are very different types of cancer that we’re dealing with.

What next steps are planned for this research and what would you like your colleagues to take away from this presentation?

Next steps include continued work, bigger rodent studies, and eventually moving into human studies. We were fortunate to be awarded a grant through the Foundation for Women’s Cancer and are continuing our work with the study. This [research] is looking at the effect of GLP-1R agonist therapy plus progesterone on endometrial cancer tumors but takes a step back and evaluates how it can affect the development of endometrial cancer and its precursor, hyperplasia. We have ongoing work [assessing whether this regimen could] prevent even the formation of hyperplasia. Can it cause regression of hyperplasia to prevent the cancer from ever growing to begin with? That’s some exciting research that we have ongoing right now.

Additionally, there’s preliminary work in our laboratory showing that one of the big markers for progesterone resistance can possibly be overcome with GLP-1R agonist therapies. That new application of this drug [class] would be exciting in this avenue because it’s a problem we run into—the longer a patient receives progesterone, the more likely they are to develop resistance and the less efficacious treatment becomes. If we can add a medication to help prolong the use [of progesterone], that’d be exciting.

References

1. Krause D, Dey D, Rai R, Benbrook DM, Chandra V. Effect of GLP-1 receptor agonist therapy in endometrial cancer. Presented at: SGO 2024 Winter Meeting. January 25-27, 2024; Olympic Valley, California. Abstract 6.
2. FDA Approves novel, dual-targeted treatment for type 2 Diabetes. FDA. News release. May 13, 2022. Accessed January 25, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-dual-targeted-treatment-type-2-diabetes