In the race to deliver therapeutics to treat brain cancer and prevent recurrence, the blood-brain barrier represents a tremendous hurdle. But brain surgery offers a way to circumvent the blood-brain barrier, allowing direct access to the site of a tumor. Working together, researchers from Brigham and Women’s Hospital (BWH) and neurosurgeons from Massachusetts General Hospital (MGH), along with colleagues at MIT, are designing a new, rapid molecular diagnostic and sustained release therapeutic that could be deployed during brain surgery to treat gliomas and prevent their return. Their results are published this week in the Proceedings of the National Academy of the Sciences.
“When a patient is in the operating room, there’s an ideal opportunity to deliver therapy,” said co-senior author Giovanni Traverso, MB, BChir, PhD, principal investigator and a physician-scientist at BWH. “But to provide the best possible therapy, we need to understand what genetic mutations we can target in that person’s tumor. We’re trying to develop a molecular diagnostic that can work fast enough to give us that information while the patient is on the operating table.”
"The first and perhaps most important step in treatment of brain tumors is the initial operation, or craniotomy, which obtains tissue to make the diagnosis, and, for lower grade lesions, provides a therapeutic benefit from removal of the tumor mass," said co-senior author Daniel Cahill, MD, PhD, associate professor of neurosurgery at MGH. "Prior studies from our group, and others, have shown that aggressive surgery provides a substantial survival benefit for patients with lower-grade gliomas. We sought to build upon this surgical scenario, attempting to further prolong survival for these patients."
Lower grade gliomas, as opposed to high-grade gliomas such as glioblastoma, tend to initially be benign but can cause disability, seizures and fatality as they grow and compress normal brain tissue. Lower grade gliomas also frequently recur and, over time, can transform into malignant brain cancer as they acquire mutations.
Recent studies have found that many lower grade gliomas harbor IDH1 and IDH2 mutations – genetic alterations that may make cancer cells vulnerable to metabolic therapeutics. However, those therapies can have toxic side effects if delivered via traditional routes.
To overcome these challenges and take advantage of the unique opportunity offered when a patient undergoes surgery to remove a glioma, Traverso, Cahill and colleagues developed a rapid genetic test that can determine if a tumor harbors an IDH1 or IDH2 mutation or several other mutations. Using previously collected patient samples, the team tested their rapid genotyping assay and found that that they could detect mutations within 27 minutes. For 75 of the 87 clinically annotated brain tumor specimens tested, the team captured the presence of one or more mutations.
In addition to the rapid diagnostic, the team has also developed a sustained release microparticle drug delivery system that can provide localized treatment and sustained protection. The team tested this delivery system in a mouse model and reported significant improvements in survival time.
The team noted that further testing of the microparticle system is needed to select the optimal formulation to advance into future clinical trials. Exploring combination therapies could further improve the effects of their local therapy approach.
This work is supported by the American Brain Tumor Association Basic Research Fellowship, the Humor to Fight the Tumor Committee, SPORE grant P50CA165962, Burroughs Wellcome Career Award in the Medical Sciences #1007616.02, NIH grant EB-000244 and the Division of Gastroenterology, Brigham and Women’s Hospital. A provisional patent application for this technology has been filed.