A rapid genetic diagnostic tool coupled with a sustained release therapeutic is being developed for lower-grade gliomas by a team of investigators.
A team of investigators from Brigham and Women's Hospital (BWH), neurosurgeons from Massachusetts General Hospital (MGH), and colleagues at Massachusetts Institute of Technology (MIT) have come together to develop a rapid genetic diagnostic tool and a sustained release therapeutic that can be released during brain surgery to treat lower-grade gliomas, or brain tumors, and prevent reoccurrence. By pairing both a diagnosis and a treatment together in 1 surgery, investigators hope to reduce the few days that it takes to diagnose and treat lower-grade gliomas down to potentially 30 minutes.
“We have developed a novel approach to the precision targeting of brain tumors in the operating room,” Giovanni Travero, MB, BChir, PhD, is an assistant professor of medicine at Harvard Medical School, and a gastroenterologist in the division of Gastroenterology at BWH, told Rare Disease ReportÒ. “Specifically, we developed a rapid molecular test which can detect mutations in approximately 30 minutes in the operating room. Furthermore, we developed a microparticle systems housing drug that could kill tumor cells.”
In the study published in the Proceedings of the National Academy of the Sciences, the team sought to improve local control of IDH mutant gliomas while simultaneously avoiding systemic toxicity associated with metabolic therapies. As Dr. Traverso explained, “Lower grade gliomas (brain tumors) are often characterized by mutations in IDH1/2 genes, which confers sensitivity to compounds targeting metabolic pathways. While the surgical goal is maximal safe resection of these tumors, invariably, residual microscopic tumor tissue that remains manifests as local recurrence in over 80% of patients with this type of tumor.”
In response to the apparent need for timely diagnosis and treatment for lower-grade gliomas, the team created a precision intraoperative treatment that pairs a rapid multiplexed genotyping tool with a sustained release microparticle (MP) drug delivery system containing an IDH-directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX-1778).
The team worked to validate the capability of their rapid genetic diagnostic tool, which they designed to determine if a tumor harbors an IDH1 or IDH2 mutation or other mutations. When testing their genotyping assay in 87 clinically annotated brain tumor specimens, they found that not only did the assay capture the presence of 1 or more mutations in 75 of the 87 specimens, it was able to detect these mutations within just 27 minutes.
The investigators then worked on testing the effectiveness of their sustained release MP drug delivery system which they had designed to deliver localized treatment and offer sustained protection. “GMX-1778 MPs showed mutation IDH genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic IDH mutant glioma murine models,” the authors write.
In surgical scenarios where control of local tumors is imperative and systemic toxicity is therapeutically limiting, the team’s strategy enables rapid intraoperative genotyping and local application of a genotype-specific treatment.
“It is worth noting that the drugs [GMX-1778] we used have been previously demonstrated to selectively kill cells with mutations in the IDH1/2 genes,” added Dr. Traverso. “These drugs, although effective, have demonstrated toxicity in the bone marrow, retina, and liver when given systemically in animal models and early human clinical trials, thereby precluding their deployment for oncologic indications.”
The team noted the need for further testing in order to establish the optimal formulation before advancing to clinical trials in humans. Simply, further safety measures need to be asserted for appropriate dosing and drug safety.
“We take safety very seriously,” said Dr. Traverso, “and our preliminary work in rodents has demonstrated an improved safety profile for the drugs when applied locally—mice with intracerebral application of sustained release formulations did not display weight loss, hematologic or hepatic findings prominently noted when administered orally to achieve a similar therapeutic dose in the brain. We are planning on further development of these and other drugs which can be applied in these new workflows by testing these in other pre-clinical models to aid in introduction of these into humans. In parallel, we have been working to achieve CLIA certification of the genotyping approach so that the molecular information of the tumor can be returned back to the surgeon in a clinically appropriate manner.”
Dr. Traverso noted that he and his team anticipate the initial human clinical trials to commence in 3 to 5 years.