Study with Lean and Obese Mice with Endometrial Cancer Paves the Way to Stage 2 Clinical Trials for a New Treatment
The Challenge
Obesity increases the risk of developing endometrial cancer, and as obesity rates rise, so do the incidence and death rates of endometrial cancer.
Certain metabolic conditions associated with obesity promote the aggressiveness of endometrial cancer, so it’s important to find drugs that are effective in endometrial cancer patients who also have obesity.
One area researchers are focusing on as a potential new target is the dopamine receptor DW (DRD2), which is a protein that detects and interacts with the hormone dopamine to affect cell growth.
DRD2 is produced at higher levels in tumors from many cancers, including breast, colon, pancreas, prostate, lymphoma, glioblastoma, and endometrial. Since treatment of endometrial cancer can be challenging, researchers want to test a recently discovered anti-cancer compound (ONC201 from Oncoeutics) that inhibits DRD2 and has had promising results in early clinical trials for certain types of advanced cancers with high DRD2 levels.
The Research
ACS grantee Victoria Bae-Jump, MD, and her lab staff hypothesize that obesity may give rise to cancers that are metabolically and clinically different from those arising in a non-obese environment. If so, obesity-influenced endometrial cancers may have unique vulnerabilities for treatment and management.
In the first obesity and endometrial cancer studies in our lab, we found that both obese mice and mice on a high-fat diet had larger and faster-growing endometrial cancers, compared to lean mice or mice on a low-fat diet. We also found that tumor cells had many more pathways to metabolize fat and glucose, showing that the tumors were using the higher level of fats in the mice's diet to grow more aggressively. In this study, we tested a new treatment in obese mice that in the future might prove to be especially helpful for women with obesity and endometrial cancer."
Her studies showed that aggressive and later stage endometrial cancers had a high level of DRD2. Working with endometrial cells in test tubes, Bae-Jump and her colleagues found that the drug ONC201 could prevent the endometrial cancer cells from growing.
They also studied whether ONC201 could stop the cancer’s growth in both obese and lean mice. The team found that untreated tumors were larger in the obese mice compared to the lean mice, showing that obesity promotes tumor growth.
After treating the mice who had endometrial cancer with the experimental drug ONC201, the size of the tumors decreased in both obese and lean mice. But the tumors in obese mice were much smaller than the tumors in lean mice, suggesting that this drug works better in obese mice. They published their results in the Journal of Experimental & Clinical Cancer Research in 2021, concluding that ONC201 inhibited cell division of endometrial cancer, tumor growth, and metastasis in both cells in the lab (in vitro) and in mice (in vivo).
Why It Matters
Obesity is a strong risk factor for endometrial cancer. Since endometrial cancer is has limited treatment options, finding drugs that are particularly effective in patients who also have obesity is important in the treatment of this type of cancer.
The fact that DRD2 levels are high in many types of cancer indicates that it may be a good target for new cancer therapies. Bae-Jump's preclinical trials provide a fundamental rationale for investigating using ONC201 to target DRD2 in endometrial cancer with phase 2 clinical trials.
It was initially surprising that ONC201 can affect several types of cancer because the gene DRD2 is typically associated with neurologic diseases. This was the first study to demonstrate the correlation between the levels of DRD2 and human endometrial cancers.
