Colorectal cancer ranks as the second leading cause of cancer-related deaths in the United States, presenting a multifaceted challenge influenced by both genetic and environmental factors. Despite advancements in treatment, there remains a pressing need for innovative therapies, particularly as cases rise among younger adults and at advanced disease stages.
One promising approach lies in epigenetics, the study of chemical modifications on DNA and its packaging proteins that influence gene expression without altering the DNA sequence. Cancer cells often display abnormal epigenetic patterns, making them an attractive target for therapeutic intervention. In recent years, drugs targeting epigenetic modifications have emerged. In particular, DNMT and EZH2 inhibitors are separate types of drugs that target specific epigenetic processes. While there has been some success using these drugs on their own, there is limited knowledge of how they would act if used together.
In a study published in Science Advances, a group of researchers from Van Andel Institute (VAI) hypothesized that using both these two types of drugs might work better together to shrink tumors in colon cancer. The research focused on a synergistic strategy, meaning the combination of the two would produce a more significant effect than either drug alone.
“DNMT inhibitors are approved to treat blood cancer while EZH2 inhibitors are approved to treat blood cancer and a rare type of sarcoma,” said VAI Professor Scott Rothbart, Ph.D. “To date, they’ve had limited individual success in solid tumors like colorectal cancer. Our findings highlight the promise of combination cancer therapies by revealing how these two medications interact, with the DNMT inhibitor priming cancer cells in a way that makes the EZH2 inhibitor more effective.”
DNMT (DNA methyltransferase) and EZH2 (histone methyltransferase) inhibitors regulate the epigenetic processes governing gene expression. In cancer, these errors enable malignant cells to survive and multiply, providing crucial targets for treatment.
DNMT inhibitor drugs, such as 5-azacytidine (AZA) and decitabine (DAC), have been cited in other studies for their effectiveness in treating certain cancers. EZH2 inhibitors have also been shown to be effective in reducing tumor growth as well as inducing antiviral activity.
In the present study, the researchers referenced earlier research indicating that DNMT inhibitors prompt cancer cells to mimic viral behavior, rendering them more vulnerable to the body’s immune system. Rothbart and his team illustrated that the combined use of DNMT and EZH2 inhibitors enhances this viral mimicry process more effectively than either drug alone. Interestingly, the upcoming trial will mark the first instance of combining these two types of medications to augment their effects on solid tumors.
“Combining medications may be a powerful way to simultaneously target multiple drivers of cancer,” Rothbart said. “In addition to revealing how DNMT and EZH2 inhibitors work together, our findings suggest that epigenetic drugs also may sensitize tumors to immunotherapy, which offers another important opportunity to enhance cancer treatment.”
The upcoming trial is supported by the Van Andel Institute-Stand Up To Cancer© Epigenetics Dream Team, which evaluates potential combination therapies for cancer, and a National Cancer Institute Specialized Programs of Research Excellence (SPORE) award, funding a team of scientists working to improve epigenetic cancer treatments.
Source: Alison A. Chomiak, et. al. Select EZH2 inhibitors enhance viral mimicry effects of DNMT inhibition through a mechanism involving NFAT:AP-1 signaling. Science Advances, March 2024.
Resource: Van Andel Research Institute. Combining epigenetic cancer medications may have benefit for colorectal cancers and other tumor types. March 27, 2024.
