Glioblastoma brain cancer, CT scan
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A team of scientists at the University of Michigan Rogel Cancer Center has identified a protein called ZMYND8 that boosts the resistance of some types of glioma to radiotherapy. Blocking the gene could lead to treatments that make radiotherapies more effective.

Glioma is one of the deadliest types of cancers, and is typically treated with a mixture of surgery, radiotherapy and chemotherapy. One subtype of the cancer involves a mutation to an enzyme called isocitrate dehydrogenase-1 (IDH1), and is less aggressive than gliomas without the mutation. However, these IDH1-mutant tumors often recur and develop resistance to radiotherapy.

In a paper published today in Clinical Cancer Research, a research team set out to identify the molecular underpinnings of radiotherapy resistance in gliomas with IDH1 mutations, and find strategies to prevent it.

The research team first sourced and cultured tumor cells from patients with IDH1-mutant glioma. They then blocked the mutated IDH1 protein with a drug and used transcriptomics and epigenomics to find out what genes were linked to the mutated enzyme.

The team found that a gene encoding a protein called ZMYND8 was downregulated when IDH1 was blocked. ZMYND8 has been previously identified as a regulator of DNA damage response, a process where the cell repairs breaks in its DNA. Since radiation kills cancer cells by damaging their DNA, IDH1-mutant gliomas might be able to resist the radiation by producing more ZMYND8. 

To confirm this hunch, the researchers treated mouse models of IDH1-mutant glioma with radiation. The mice that also had a mutation knocking out ZMYND8 had better outcomes with radiotherapy than mice with ZMYND8 intact.

Finally, the team tested the effects of drugs that target DNA damage response, such as the PARP inhibitor pamiparib, which is approved in China to treat subtypes of late-stage ovarian cancer. They found that blocking ZMYND8 in cancer cells worked synergistically with pamiparib and similar drugs, making the tumor more susceptible to radiation.

With more research, the authors aim to develop RNA-based blockers of ZMYND8 that boost the effect of radiotherapy on IDH1 mutant glioma, improving the outlook for these patients. In a previous project, some of the researchers worked on using nanoparticles to deliver a protein drug across the blood-brain barrier to treat brain cancer. The same technique could be used to deliver RNA-based ZMYND8 inhibitors.

Additionally, this approach could be combined with PARP inhibitors to further supercharge the anti-cancer effect of radiotherapy on IDH1-mutant gliomas.

“These tumors almost always recur, and when they do, the tumors are much more aggressive,” said Maria Castro, professor of neurosurgery at Michigan Medicine and senior author on the study, in a public statement. “This finding gives us a new therapeutic avenue to treat these patients. It’s a very promising and novel therapeutic target.” 

Blockers of DNA damage response are already being trialed in the fight against forms of glioma. In 2021, for example, the PARP inhibitor olaparib, marketed to treat forms of ovarian cancer, missed the primary endpoint in a phase 2 trial for the treatment of IDH-mutant glioma.

Members of the University of Michigan group have also identified drug targets for sensitizing other forms of mutated glioma to radiotherapy in previous projects. One is the protein ATM, which can be blocked to improve survival after radiotherapy in glioma patients with a mutated form of the protein ATRX.

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