A targeted approach to treating glioma

(This mutation is usually seen in gliomas that strike adults under the age of 45.) The researchers have devised a way to rapidly check for the mutation during brain surgery, and if the mutation is present, they can implant microparticles that gradually release the drug over several days or weeks.

“To provide really effective therapy, we need to diagnose very quickly, and ideally have a mutation diagnosis that can help guide genotype-specific treatment,” said Giovanni Traverso, an assistant professor at Brigham and Women’s Hospital, Harvard Medical School, a research affiliate at MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the paper.

The researchers are also working ways to identify and target other mutations found in gliomas and other types of brain tumours.

“This paradigm allows us to modify our current intraoperative resection strategy by applying molecular therapeutics that target residual tumour cells based on their specific vulnerabilities,” said Ganesh Shankar, who is currently completing a spine surgery fellowship at Cleveland Clinic prior to returning as a neurosurgeon at Massachusetts General Hospital, where he performed this study.

Shankar and Koch Institute postdoc Ameya Kirtane are the lead authors of the paper, which appears in the Proceedings of the National Academy of Sciences. Daniel Cahill, a neurosurgeon at MGH and associate professor at Harvard Medical School, is a senior author of the paper, and Robert Langer, the David H. Koch Institute Professor at MIT, is also an author.

The tumours that the researchers targeted in this study, historically known as low-grade gliomas, usually occur in patients between the ages of 20 and 40.

During surgery, doctors try to remove as much of the tumour as possible, but they can’t be too aggressive if tumours invade the areas of the brain responsible for key functions such as speech or movement. The research team wanted to find a way to locally treat those cancer cells with a targeted drug that could delay tumour regrowth.

To achieve that, the researchers decided to target a mutation called IDH1/2. Cancer cells with this mutation shut off a metabolic pathway that cells normally use to create a molecule called NAD, making them highly dependent on an alternative pathway that requires an enzyme called NAMPT. Researchers have been working to develop NAMPT inhibitors to treat cancer.

So far, these drugs have not been used for glioma, in part because of the difficulty in getting them across the blood-brain barrier, which separates the brain from circulating blood and prevents large molecules from entering the brain.

NAMPT inhibitors can also produce serious side effects in the retina, bone marrow, liver, and blood platelets when they are given orally or intravenously.

To deliver the drugs locally, the researchers developed microparticles in which the NAMPT inhibitor is embedded in PLGA, a polymer that has been shown to be safe for use in humans. Another desirable feature of PLGA is that the rate at which the drug is released can be controlled by altering the ratio of the two polymers that make up PLGA — lactic acid and glycolic acid.

To determine which patients would benefit from treatment with the NAMPT inhibitor, the researchers devised a genetic test that can reveal the presence of the IDH mutation in approximately 30 minutes.

This allows the procedure to be done on biopsied tissue during the surgery, which takes about four hours. If the test is positive, the microparticles can be placed in the brain, where they gradually release the drug, killing cells left behind during the surgery.

In tests in mice, the researchers found that treatment with the drug-carrying particles extended the survival of mice with IDH mutant-positive gliomas. As they expected, the treatment did not work against tumours without the IDH mutation.

In mice treated with the particles, the team also found none of the harmful side effects seen when NAMPT inhibitors are given throughout the body.

“When you dose these drugs locally, none of those side effects are seen,” Traverso said. “So not only can you have a positive impact on the tumour, but you can also address the side effects which sometimes limit the use of a drug that is otherwise effective against tumours.”

The approach builds on similar work from Langer’s lab that led to the first FDA-approved controlled drug-release system for brain cancer — a tiny wafer that can be implanted in the brain following surgery.

“I am very excited about this new paper, which complements very nicely the earlier work we did with Henry Brem of Johns Hopkins that led to Gliadel, which has now been approved in over 30 countries and has been used clinically for the past 22 years,” Langer said.

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Image credit: MIT.