An upcoming trial in patients with colorectal cancer will be the first to test an DNMT inhibitor and an EZH2 inhibitor together in any type of cancer.
A pair of epigenetic cancer drugs packs a “one-two punch” against colorectal tumors to knock them out more effectively than either medication alone, a new study in cells suggests.
In a journal article published March 27 in Science Advances, a team of researchers led by scientists from the Van Andel Institute in Grand Rapids, Michigan showed that a low dose of the DNA methyltransferase (DNMT) inhibitor decitabine combined with Tithe EZH2 inhibitor tazemetostat successfully induced changes that would make cancer cells more vulnerable to destruction by the immune system. The chemotherapy decitabine is commercialized by Eisai as Inqovi; tazemetostat is commercialized by Ipsen as Tazverik. Neither company was involved in the study.
While agents in both classes of drugs are FDA approved to treat blood cancer, they haven't had much success in solid tumors such as colorectal cancer, Scott Rothbart, Ph.D., the study’s corresponding author, said in a press release. “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.”
“Epigenetic” is a term that refers to typically reversible modifications made to genes that do not directly alter the genes themselves, but rather affect their expression. Cancer progression involves many epigenetic changes both to the cancer cells themselves and to the immune cells that would otherwise destroy them.
Scientists have attempted to destroy cancer by countering these changes pharmacologically and restoring the expression of anti-cancer genes. The most established means of doing so is with histone deacetylase inhibitors, or HDAC inhibitors, such as Merck’s Zolinza (vorinostat) for lymphoma and Acrotech Biopharma’s Beleodaq (belinostat) for myeloma. The only other FDA-approved DNMT inhibitor besides Inquovi is Celgene’s acute myeloid leukemia drug Vidaza (azacitidine). Tazverik is the sole EZH2 inhibitor with FDA approval.
Earlier work by Van Andel Institute researchers showed that DNMT inhibitors cause cancer cells to act as though they’ve been infected by a virus, making them more vulnerable to one’s immune system. For the new study, the researchers hypothesized that because DNMT inhibitors alter the cells in a way that could make EZH2 inhibitors more effective, they would work better together than separately.
To see whether this was the case, the researchers started by testing them against different types of colorectal cancer cells on their own, then looked at them in combination. The results backed up their rationale: EZH2 inhibitors compounded the changes initiated by the DNMT inhibitors, boosting the duo’s effectiveness.
The findings are the basis for an upcoming clinical trial that will evaluate the pair against colorectal cancer in patients. Combinations of DNMT inhibitors and HDAC inhibitors have been tested in clinical trials to mixed results, the study noted. The new trial will be the first to evaluate a DNMT inhibitor and an EZH2 inhibitor.
Future studies should evaluate the pair with immunotherapies, too, Rothbart noted in the release. There’s evidence in preclinical models that the viruslike changes the drugs make in the cells could lead to a better response to drugs that boost the immune system.
“These data suggest future directions for testing whether DAC and TAZ treatments might improve tumor response to immunomodulating agents,” the researchers wrote in the study.
