It’s a good news, bad news story. Patients whose brain tumors have a mutated enzyme called IDH1 tend to live longer than those without the mutation. But even though these tumors are initially less aggressive, they always come back. An important reason: the tumors are resistant to radiation and are invasive.
In a new study, researchers at the University of Michigan Rogel Cancer Center have discovered a gene that is overexpressed in mutated IDH1. Studies in human cells and a new mouse model both show that this gene, called ZMYND8, plays a critical role in radiation resistance. When they knocked down the gene, the glioma cells responded to radiation.
“These tumors almost always come back, and when they do, the tumors are much more aggressive. This finding gives us a new therapeutic avenue to treat these patients. It is a promising new therapeutic target,” said Maria G. Castro, Ph.D., RC Schneider Collegiate Professor of Neurosurgery at Michigan Medicine Castro is senior author of the study, published in Clinical cancer researcha journal of the American Association for Cancer Research.
The researchers used two cell cultures obtained from surgical biopsies of patients with mutated IDH1 glioma. Cells were treated with an inhibitor designed to block a metabolite produced by the mutated IDH1. From there, they screened the RNA and found a gene called ZMYND8.
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“After treatment with the mIDH1 inhibitor, we found that this gene, ZMYND8, was significantly downregulated. It is overexpressed in mutant IDH1 glioma cells, but when you treat the cells with an inhibitor, the expression of the ZMYND8 protein drops. And when this gene goes down, the cells become radiosensitive,” said first author Stephen V. Carney, a graduate student in Cancer Biology in the Castro/Lowenstein Lab.
ZMYND8 is known to be a regulator of DNA damage response. Radiotherapy works by damaging DNA. When ZMYND8 protein expression is high, researchers saw radiation resistance. When ZMYND8 was knocked out, the radiation led to DNA damage and increased glioma cell death.
The researchers also developed a new mouse model of mutated IDH1 glioma, which confirmed that knocking out ZMYND8 sensitized the tumors to radiation therapy, leading to increased survival.
“ZMYND8 contributes to survival of mutant IDH1 glioma in response to radiation. Our study shows that we now have a new way to treat these tumors by using mRNA-based therapies, where we can downregulate ZMYND8 expression to make the cells radiosensitive,” said study author Pedro R. Lowenstein, MD. , Ph.D. , Richard C. Schneider Collegiate Professor of Neurosurgery at Michigan Medicine.
The researchers also combined ZMYND8 knockdown with other cancer drugs, such as PARP and HDAC inhibitors. They found that these other drugs were synergistic in making the cells more responsive to radiation, suggesting potential for combination therapy for patients with mutant IDH1 glioma.
More research is needed, but Castro envisions working with colleagues at the UM Biointerfaces Institute to design RNA-based inhibitors targeting ZMYND8, which can be delivered using nanoparticles specifically designed to address the challenging breaking the blood-brain barrier. It is a technique that they have already tested in previous research.
Reference: Carney SV, Banerjee K, Mujeeb A, et al. Zinc finger MYND type with 8 (ZMYND8) is epigenetically regulated in mutant Isocitrate Dehydrogenase 1 (IDH1) glioma to promote radioresistance. Clin. cancer res. 2023: CCNR-22-1896. doi: 10.1158/1078-0432.CCR-22-1896
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