{"id":28358,"date":"2022-09-26T12:00:00","date_gmt":"2022-09-26T12:00:00","guid":{"rendered":"https:\/\/www.cancer.gov\/news-events\/cancer-currents-blog\/2022\/glioma-treatment-targeting-pyrimidine-synthesis"},"modified":"2024-11-03T15:13:15","modified_gmt":"2024-11-03T15:13:15","slug":"vulnerability-in-brain-tumors-may-open-door-to-new-treatments","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/vulnerability-in-brain-tumors-may-open-door-to-new-treatments\/","title":{"rendered":"Vulnerability in Brain Tumors May Open Door to New Treatments"},"content":{"rendered":"

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To explore potential treatments for gliomas, researchers developed models called organoids (pictured) using tumor samples donated by people with these lethal brain cancers.<\/p>\n

Credit: Used with permission from Kalil Abdullah, M.D.<\/p>\n<\/p><\/div>\n<\/figcaption><\/figure>\n<\/p><\/div>\n

Two new studies have uncovered a vulnerability in different forms of brain tumors that may make the cancers susceptible to the same treatments. The brain tumors are gliomas, which are among the most lethal cancers.<\/p>\n

One study focused on diffuse midline gliomas, which occur most often in children. The other study focused on gliomas with mutations<\/a> in the IDH1<\/em> or IDH2<\/em> genes<\/a>, which tend to occur in adults.<\/p>\n

Both investigations led to a similar insight: Some gliomas become dependent for their survival on one of the ways that cells produce chemicals called pyrimidine<\/a> nucleotides, which are components of DNA<\/a>.<\/p>\n

The dependence of certain glioma cells on this process, called de novo pyrimidine nucleotide synthesis, creates a vulnerability. And the new research suggests that a drug may be able to exploit this vulnerability for the benefit of patients with gliomas. <\/p>\n

In both studies, a drug called BAY 2402234 penetrated the brains of mice with gliomas and shrank their tumors, though by different mechanisms. Results from the NCI-supported studies were published in Cancer Cell<\/em> on August 18.<\/p>\n

Based on the findings, both teams of investigators are planning clinical trials<\/a> to test the drug in people with diffuse midline glioma or IDH<\/em>-mutant glioma. <\/p>\n

\u201cThis drug prevents the formation of one of the building blocks of DNA, reducing the ability of cancer cells to divide or repair themselves and leading to cell death,\u201d said Mioara Larion, Ph.D., of NCI\u2019s Center for Cancer Research<\/a>, who studies brain tumors but had no role in the new studies.<\/p>\n

The finding that \u201ctwo vastly different brain tumors share a common vulnerability was unexpected and very interesting,\u201d Dr. Larion continued. \u201cWe and others are excited about the possibility of using inhibitors that target certain metabolic pathways to treat patients.\u201d <\/p>\n

Desperate need for new treatments<\/h2>\n

Gliomas are the most common brain tumor among adults. The cancer is usually fatal, and no new drugs have been approved for the disease over the past decade.<\/p>\n

\u201cThere is a desperate need for new treatments for glioma brain tumors,\u201d said Diana Shi, M.D., of the Dana-Farber Cancer Institute, and a member of the team that conducted the study of gliomas with IDH<\/em> mutations.<\/p>\n

Dr. Shi and her colleagues identified BAY 2402234 while screening hundreds of compounds for their ability to slow the growth of IDH<\/em>-mutant glioma cells. The drug, which has been tested in people with leukemia, blocks the activity of an enzyme<\/a> called DHODH, which is involved in pyrimidine synthesis.<\/p>\n

In experiments with mouse models, the drug inhibited the growth of IDH<\/em>-mutant gliomas but not gliomas without the mutations<\/a>.<\/p>\n

In glioma cells, IDH<\/em> mutations can cause DNA damage when there is an imbalance in the level of nucleotides. These imbalances are caused by blocking pyrimidine synthesis, the researchers found.<\/p>\n

They also observed that genes involved in sensing and repairing DNA damage were less active in IDH<\/em>-mutant gliomas than in gliomas without these mutations.  <\/p>\n

\u201cWe believe that patients with IDH<\/em>-mutant gliomas may benefit from treatments that target … DHODH,\u201d said Samuel McBrayer, Ph.D., of the Children\u2019s Medical Center Research Institute at UT Southwestern, who co-led the study with William G. Kaelin, Jr., M.D., of Dana-Farber.<\/p>\n

As a next step, the researchers are working to reach an agreement with the developers of BAY 2402234, the Broad Institute and Bayer Pharmaceuticals, to launch a clinical trial of the drug in people with certain types of glioma. <\/p>\n

The trial will be sponsored by NCI\u2019s Glioblastoma Therapeutics Network<\/a> (see box) and will focus on a type of glioma called grade 4 IDH<\/em>-mutant astrocytoma<\/a>.<\/p>\n

Developing new models of gliomas<\/h2>\n

A challenge in developing treatments for gliomas has been the limited number of models for assessing how a drug may affect a brain tumor.<\/p>\n

\u201cWe don\u2019t have a great way to evaluate new drugs before they are tested in patients who have gliomas, and this has been a real bottleneck in the research,\u201d said Kalil Abdullah, M.D., a neurosurgeon who specializes in treating brain tumors at the University of Pittsburgh\u2019s Hillman Cancer Center.<\/p>\n

To address this challenge, his laboratory has developed models called surgically explanted organoids, which are tiny 3-dimensional representations of a patient\u2019s tumor. These models are derived from tissue samples collected during brain surgery, and they retain many of the biological characteristics of the original tumor<\/a>.<\/p>\n

In the new study, BAY 2402234 preferentially killed organoids created from IDH<\/em>-mutant gliomas relative to organoids created from gliomas that lacked the mutations. <\/p>\n

\u201cAs far as we know, this was the first study to use organoids developed from patients with lower-grade gliomas to evaluate a new drug,\u201d said Dr. Abdullah. \u201cAnd the results were very promising.\u201d<\/p>\n

Urgent need for progress against gliomas in children<\/h2>\n

As with gliomas in adults, there has been little progress in developing new treatments for gliomas that occur in children. The category of diffuse midline gliomas includes aggressive tumors known as diffuse intrinsic pontine gliomas, which occur most often in children and are almost uniformly fatal.<\/p>\n