ARTICLE IN BRIEF
Investigators used a novel therapeutic — which was small and nimble enough to cross the blood-brain barrier — to target specific oncogenes in cells of mice with glioblastoma multiforme; the therapy increased their survival rate by nearly 20 percent and reduced tumor size by three- to four-fold, as compared with the control group.
Researchers have demonstrated a way to use nanotechnology to deliver an RNA interference-based therapy designed to silence a gene involved in glioblastoma, the most lethal type of brain tumors.
The approach was shown to work both in cell culture and animal studies, and researchers at Northwestern University hope to eventually move testing into humans. The therapy targets the oncogene Bcl2Like12 (Bcl2L12), which is overexpressed in glioblastoma tumors.
The research team reported in the October 30 edition of Science Translational Medicine that when the drug was injected into mice with human glioblastoma, their tumors shrank and they had increased survival compared with control mice.
The proof-of-concept research showed that the drug is able to penetrate both the blood-brain barrier and the brain-tumor barrier and disseminate throughout tumor tissue.
Glioblastoma multiforme (GBM) has been proven to be a particularly tough cancer for researchers to tackle, and treatment advances have been modest. The cancer kills about 13,000 people in the US each year and the median time from diagnosis to death is about 14 to 16 months. Recurrence almost always happens.
A big challenge in drug development is getting therapies to cross the blood-brain barrier and then on into tumor cells.
The researchers at Northwestern developed a novel RNAi-based nanotechnological platform, termed spherical nucleic acid (SNA). The nanoconjugates consist of a golden nanoparticle core surrounded by small interfering RNA (siRNA) engineered to turn off the expression on the Bcl2L12 oncogene. The investigators identified Bcl2L12 as a potential prognostic factor, because GBM patients with high-level overexpression of Bcl2L12 were shown in a database to have shorter progression-free survival compared to patients with “intermediate” (0.5- to 4-fold) expression or underexpression of Bcl2L12.
The investigators reported that the SNAs efficiently entered primary and transformed glial cells in vitro. The SNAs penetrated the blood-brain barrier and blood-tumor barrier in vivo to disseminate throughout xenogeneic glioma explants. SNAs targeting the oncoprotein Bcl2Like12 (Bcl2L12) were effective in knocking down endogenous Bcl2L12 mRNA and protein levels, and sensitized glioma cells toward therapy-induced apoptosis by enhancing effector caspase and p53 activity. Further, systemically delivered SNAs reduced Bcl2L12 expression in intracerebral GBM, increased intratumoral apoptosis, and reduced tumor burden and progression in xenografted mice, without adverse side effects.
“We believe this is the first report of a method to systematically deliver RNA interference to a brain tumor,” said Alexander H. Stegh, PhD, assistant professor of neurology at Northwestern and coauthor of the study, told Neurology Today. He said that when the biotherapeutic was injected into mice “we saw a three- to four-fold reduction in tumor burden and a 20 percent increase in overall survival.” There did not appear to be any toxic effects.
“This work establishes spherical nucleic acids [SNAs] as a promising new class of therapeutic agents capable of treating disease through systemic injection,” his team concluded in the journal report. Further testing of the safety and effectiveness of the drug in non-human primates is being planned as the next step toward testing in humans.
Jeffrey J. Raizer, MD, another Northwestern neurologist who is involved in the research but not on this particular paper, said glioblastoma has eluded effective treatment in part because it's a complex disease involving multiple genes and molecular pathways.
Also, its very location makes it difficult to target with drugs. Standard treatment, including surgery, radiation and the chemo agent temozolomide, only increase survival time incrementally.
“It's probably not one disease. It's probably multiple diseases,” said Dr. Raizer, professor of neurology and medicine-hematology/oncology.
He said the new drug under development at Northwestern might have the potential to enhance the effectiveness of other treatments already in use for glioblastoma. The SNA platform used for glioblastoma could also be reconfigured to target other cancers, such as melanoma, Dr. Raizer said.
Lisa M. DeAngelis, MD, chair of neurology at Memorial Sloan-Kettering Cancer Center, told Neurology Today that “this study is very exciting because it establishes proof of principle.”
“I think all of these novel approaches to both drug delivery and hitting abnormal targets in the tumor cells are very exciting, but it remains to be seen if this is going to translate into the human situation,” she said. “There have been a lot of promising results in animals that haven't yet led to a major therapeutic advance in human disease.”
Dr. DeAngelis, who is a neuro-oncologist, said there is still much to be learned about the genetics of glioblastoma and which genes will be most effective to target in therapy.
“A fundamental issue is to figure out which of the many abnormalities are the driver mutations as opposed to passenger mutations,” Dr. DeAngelis said. “You can turn off a number of passenger mutations, but that won't impede tumor growth if the driver mutations are unaffected.”
Matthias Gromeier, MD, associate professor in the department of neurosurgery at Duke University Medical Center, said that while he found the research to be “technically competent” he does not think siRNA therapy holds much promise for treating glioblastoma. “They saw modest effects,” he said, and the treatment effects appeared to be transient.
“Glioblastoma is a tumor that is notoriously difficult to target with anything,” Dr. Gromeier said. He said the cancer tends to be resistant to radiation and chemotherapy, and even in cases where a localized tumor appears to have been completely resected, tumor cells likely have already infiltrated elsewhere in the brain.
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