Cutting off a process that cancerous cells rely on can force them to stop growing.

MIT biologists have discovered a fundamental mechanism that helps brain tumors called glioblastomas grow aggressively. After blocking this mechanism in mice, the researchers were able to halt tumor growth.

The researchers also identified a genetic marker that could be used to predict which patients would most likely benefit from this type of treatment. Glioblastoma is usually treated with radiation and the chemotherapy drug temozolamide, which may extend patients’ lifespans but in most cases do not offer a cure.

“There are very few specific or targeted inhibitors that are used in the treatment of brain cancer. There’s really a dire need for new therapies and new ideas,” said Michael Hemann, an associate professor of biology at MIT, a member of MIT’s Koch Institute for Integrative Cancer Research, and a senior author of the study.

Drugs that block a key protein involved in the newly discovered process already exist, and at least one is in clinical trials to treat cancer. However, most of these inhibitors do not cross the blood-brain barrier, which separates the brain from circulating blood and prevents large molecules from entering the brain. The MIT team hopes to develop drugs that can cross this barrier, possibly by packaging them into nanoparticles.

The study, which appeared in the journal Cancer Cell on September 28, is a collaboration between the labs of Hemann; Jacqueline Lees, associate director of the Koch Institute and the Virginia and D.K. Ludwig Professor for Cancer Research; and Phillip Sharp, an MIT Institute Professor and member of the Koch Institute. The paper’s lead authors are former MIT postdoc Christian Braun, recent PhD recipient Monica Stanciu, and research scientist Paul Boutz.

Several years ago, Stanciu and Braun came up with the idea to use a type of screen known as shRNA to seek genes involved in glioblastoma. This test involves using short strands of RNA to block the expression of specific genes. Using this approach, researchers can turn off thousands of different genes, one per tumor cell, and then measure the effects on cell survival.

One of the top hits from this screen was the gene for a protein called PRMT5. When this gene was turned off, tumor cells stopped growing. Previous studies had linked high levels of PRMT5 to cancer, but the protein is an enzyme that can act on hundreds of other proteins, so scientists weren’t sure exactly how it was stimulating cancer cell growth.

Further experiments in which the researchers analyzed other genes affected when PRMT5 was inhibited led them to hypothesize that PRMT5 was using a special type of gene splicing to stimulate tumor growth. Gene splicing is required to snip out portions of messenger RNA known as introns, that are not needed after the gene is copied into mRNA.

In 2015, Boutz and others in Sharp’s lab discovered that about 10 to 15 percent of human mRNA strands still have one to three “detained introns,” even though they are otherwise mature. Because of those introns, these mRNA molecules can’t leave the nucleus.

“What we think is that these strands are basically an mRNA reservoir. You have these unproductive isoforms sitting in the nucleus, and the only thing that keeps them from being translated is that one intron,” said Braun, who is now a physician-scientist at Ludwig Maximilian University of Munich.

In the new study, the researchers discovered that PRMT5 plays a key role in regulating this type of splicing. They speculate that neural stem cells utilize high levels of PRMT5 to guarantee efficient splicing and therefore expression of proliferation genes. “As the cells move toward their mature state, PRMT5 levels drop, detained intron levels rise, and those messenger RNAs associated with proliferation get stuck in the nucleus,” Lees said.

When brain cells beco