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Precision Medicine Technique Devised for Brain Tumors

Brain tumor graphic

(National Science Foundation)

7 August 2018. A process for quickly determining genetic mutations behind brain tumors and delivering a treatment addressing those mutations is shown to extend the survival of lab mice induced with those tumors. Medical researchers and engineers at Massachusetts Institute of Technology and hospitals affiliated with Harvard Medical School describe their techniques in yesterday’s issue of Proceedings of the National Academy of Sciences (paid subscription required).

The team from the MIT biomaterials science and engineering lab led by Robert Langer and researchers at Massachusetts General and Brigham and Women’s hospitals in Boston are seeking better therapy options for people with gliomas, a type of tumor that affects glial cells in the brain. Glial cells surround and support the signaling functions of nerve cells in the brain. The standard treatment for gliomas today is surgery to remove the tumor, which must be done carefully to prevent damaging vital brain functions. As a result, surgery often leaves behind cancer cells that allow the tumor to return.

Between 20 and 25 percent of these gliomas can be traced to mutations in the isocitrate dehydrogenase 1 or IDH1 and IDH2 genes, also associated with metabolic functions in the body. While these specific mutations could possibly be treated with inhibitors that block the pathway for proteins from these mutations, giving this therapy through the blood stream could damage bone marrow, the liver, retinas, and blood platelets. The drugs would also have trouble crossing the blood-brain barrier. The researchers decided to develop a method for delivering these inhibitors directly into the region of the brain where the tumor occurred, immediately after its removal.

The team led by Langer, Mass. General neurosurgeon Daniel Cahill, and gastroenterologist/biomedical engineer Giovanni Traverso at Brigham and Women’s hospital first needed a way of determining the precise mutations responsible for the tumor. They assembled a set of genetic analysis tests to identify the mutations responsible for the tumor from biopsy samples in about 30 minutes.

The team also designed a method for delivering a small-molecule drug code-named GMX-1778 that inhibits the pathway producing proteins released by IDH1 and IDH2 mutations directly into the brain. In this case, the drug is formulated into microparticles embedded in poly lactic-co-glycolic acid, or PLGA, a common, biocompatible polymer used for time-released drug delivery. The PLGA microparticles are then inserted into the affected brain area for slow release after the tumor is removed.

The team designed this genetic testing and microparticle delivery process to be done at the same time the patient’s brain tumor is removed, a procedure taking about 4 hours. The researchers first  tested the process in simulated lab cultures, then in mice induced with gliomas resulting from IDH1 and IDH2 mutations. The mice with the mutations receiving the microparticle treatments survived longer, and with no indication of adverse effects from the inhibitors, than mice without the mutations.

The researchers plan further preclinical tests of these techniques with larger animals, but believe the process can be applied to other types of tumors where there’s a clear link to specific mutations. “We feel its best use would be in the early stages, to improve local control and prevent regrowth at the site,” says Cahill in an MIT statement. “Ideally it would be integrated early in the standard-of-care treatment for patients, and we would try to put off the recurrence of the disease for many years or decades.”

Several of the researchers, including the senior authors, filed a provisional patent on the technology. The following video tells more about the techniques.

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