In This Article
- Mass General researchers have discovered that in the majority of patients who undergo resection of lower-grade glioma, disease progression is due to regrowth at the surgical site
- Working with MIT, the researchers developed drug microparticles designed to be administered at the tumor site during surgery
- Studies in human cell lines showed that the microparticles are effective only against IDH-mutant glioma
- The research team developed a rapid diagnostic assay that can distinguish IDH-mutant glioma from IDH wild-type glioma within 30 minutes
- In a mouse model of IDH-mutant glioma, a single intracranial injection of the novel microparticles suppressed tumor growth
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Lower-grade glioma is often characterized by mutations in the metabolism-related genes IDH1 or IDH2. The best initial therapy for these tumor is aggressive neurosurgical resection, which removes as many tumor cells as possible, and provides a longer time before the tumor regrows. Preventing this regrowth is critical for patient survival. A Mass General research team led by neurosurgeons Ganesh Shankar MD, PhD, and Daniel Cahill, MD, PhD, recently found that 82% of patients who underwent resection of IDH-mutant glioma experienced tumor regrowth within 2 cm of the initial tumor margin. This local failure was a harbinger of poor prognosis.
Dr. Cahill’s group wondered whether it would be feasible to administer a genotype-targeted drug at the surgical site during glioma resection to improve patient outcomes. Previously, they had established that IDH-mutated cancers are sensitive to a certain type of metabolism-targeted therapy: small molecules that inhibit nicotinamide phosphoribosyltransferase (NAMPT).
Unlike traditional genotoxic chemotherapeutics, NAMPT inhibitors can selectively kill tumor cells without a requirement for DNA damage and cell-cycle replication. This makes them well-suited to treating the slow-growing indolent phase of lower-grade glioma. However, systemic administration of NAMPT inhibitors to treat glioma is impractical because of dose-limiting hematologic and gastrointestinal toxicities.
Building a Better Drug
Dr. Shankar worked with Giovanni Traverso, MD, PhD, Ameya Kirtane, PhD, and Robert Langer, ScD of MIT, in the largest bioengineering laboratory in the world. The Langer Lab has previously developed a series of novel drug delivery technologies that have been approved by the Food and Drug Administration (FDA) for treatment of glioblastoma. “Working together with the amazing team from MIT, we’ve created a specialized kind of microparticle that secretes a drug specific to IDH-mutant glioma,” Dr. Shankar said.
In their collaboration with the Mass General group, the bioengineers started with a backbone made of poly(lactic-co-glycolic) acid, a safe and biodegradable copolymer that is used in multiple FDA-approved drugs. They mixed in NAMPT inhibitors that Dr. Cahill’s team has discovered to be very selective for IDH-mutant tumors.
Efficacy in Cell Lines
Dr. Cahill and his colleagues tested the sustained-release microparticles in cell lines derived from patients with glioma. They observed that the NAMPT inhibitors particles had a strong anti-cancer effect in IDH-mutant glioma cells, but not control glioma cells with normal IDH.
The researchers realized that they would need to distinguish IDH1-mutant tumors from IDH1 wild-type tumors during surgery prior to administering the new local therapy.
“Right now, in most situations, the patient has surgery and then the pathology team reports the genetic result about a week later,” Dr. Cahill said. “Even at Mass General, it takes about a day to get the answer. We have to accelerate that determination to be so fast that the information can be used during the operation.”
Intraoperative Diagnostic Tool
The researchers had previously developed a rapid intraoperative genotyping assay for glioma. They broadened its diagnostic capability so that it can detect common glioma mutations (IDH1, two TERT promoter variants, H3F3A K27M, and BRAF V600E) within 30 minutes.
When the new genotyping assay was applied to tumor specimens, detection of IDH1 mutations at the R132 codon was 100% concordant with the results of immunohistochemistry. Furthermore, the assay could capture additional IDH1 mutations that would have been negative by standard immunohistochemistry testing. Dr. Shankar validated their assay on 87 brain tumor specimens, finding that 75 (86%) of them were captured by the presence of one or more mutations. When the specimens were restricted to tumors with diffuse glioma histology, more than 90% were positively assigned.
Studying the Microparticles in Mice
The next step was for the team to test the NAMPT microparticles in vivo. Earlier, when NAMPT inhibitors had been administered intravenously to non-tumor-bearing mice, they had exhibited substantial toxicity. But when NAMPT particles were injected intracranially, non-tumor-bearing mice developed no toxicities, including no seizures or local infections. Two days after injection, NAMPT inhibitors levels in brain were below the limit of detection, demonstrating that the drug had been safely cleared.
Finally, the researchers tested whether the microparticles would affect tumor growth. They engineered IDH1-mutant and IDH wild-type glioma cells to express firefly luciferase (the substance that makes a firefly glow) and implanted them intracranially. Fifteen days later, bioluminescence imaging confirmed invasive tumor growth, similar to what is noted in humans.
Strikingly, only one intratumoral injection of NAMPT microparticles was needed to suppress the growth of IDH-mutant tumors, compared to the results of injecting blank microparticles. In IDH-mutant tumors, treatment also resulted in significantly improved median survival. As expected, injection of NAMPT inhibitor particles did not affect tumor growth or survival in the mice with IDH wild-type glioma.
The Future of Glioma Treatment
Dr. Cahill acknowledged that several groups are competing to develop different diagnostic methods that rapidly identify IDH-mutant tumors, either intraoperatively or preoperatively on MRI scans. “Certainly we are trying to optimize our diagnostics so that they can be used broadly,” he said. “But ultimately, the most important thing is to improve outcomes for the patients. There might be other diagnostic methods in the future, which are better than ours. What we would still argue is, whatever method you use, make the decision to give the particles as soon as the information becomes available.”
His team is currently studying the optimal formulation of microparticles to advance into clinical trials.
“The push of genetic targeted treatments into the OR is going to happen,” Dr. Cahill predicts. “There are so many competing technologies. There’s no getting around the fact that this is the future. I believe strongly that, five years from now, doctors are going to have routine access to their patient’s molecular information during the operation.”
For their development of the genotype-based local glioma therapy, Dr. Shankar and his colleagues were presented with the Mahaley Clinical Research Award during the 2018 annual meeting of the American Association of Neurological Surgeons.
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