U.Va. researchers developed an experimental approach to treating glioblastoma — the most common and deadliest brain cancer — according to a U.Va. Health press release published July 22. The treatment uses microRNAs to shut down multiple cancer-driving genes at once and focused sound waves to open a path through the brain’s natural defenses without surgery.
This experimental treatment approach has been tested in mice, and U.Va. researchers say that human clinical trials are at least a few years away. The human trials are delayed in part due to the large amount of funding needed to manufacture a version safe to test on human patients.
Dr. Roger Abounader, professor in the School of Medicine’s Department of Microbiology, Immunology and Cancer Biology and a member of both the U.Va. Comprehensive Cancer Center and the Center for RNA Science and Medicine, led the research. The study, whose first author is senior research scientist Shekhar Saha, was published June 30 in the Journal of Clinical Investigation.
According to a U.Va. Health press release, glioblastoma kills more than 13,000 people in America every year. According to the published study, even with surgery, radiation and chemotherapy, patients survive an average of about 15 months.
It is difficult to treat for two reasons, as explained in the press release. First, the tumors thread through healthy brain tissue, making them nearly impossible to fully remove through surgery. Second, most treatments cannot reach the brain at all due to the blood-brain barrier — a lining that lets small, fat-soluble molecules enter the brain, while blocking nearly everything else. The barrier blocks anti-tumor drugs the same way it blocks harmful substances and pathogens.
The study also noted that the standard treatment is for patients to undergo surgery to remove as much of the tumor as possible, followed by radiation and chemotherapy.
Existing drugs for glioblastoma block one malfunctioning molecule at a time. That approach does not fully control the cancer, Abounader said, because the tumor is driven by many genes at once.
“In any single glioblastoma tumor, many genes are deregulated at the same time, and several of them drive tumor growth,” Abounader said. “If you inhibit one, the others will compensate and take over and continue to drive tumor growth.”
Abounader’s team instead uses microRNAs — small molecules that occur naturally in the body but can also be made in a lab for use as a treatment. A microRNA quiets overactive genes by binding to the messenger RNA, which carries a working copy of the gene’s instructions, and blocking it before the gene’s protein can be made. Since one microRNA can bind many different messenger RNAs, a single molecule can turn down multiple cancer-driving genes at once.
“One single microRNA molecule can regulate the expression of several genes at the same time,” Abounader said.
Targeting several genes with a single microRNA is theoretically equivalent to giving a patient a combination of several drugs, according to the study — without the rise in toxicity that combining cancer drugs typically causes.
The treatment approach is designed as precision medicine, meaning the treatment would differ from patient to patient.
“The idea is to find out what genes are deregulated in any individual patient and then find the microRNA that targets them,” Abounader said.
Abounader said his team created an algorithm that, for each patient, identifies a single microRNA capable of targeting several of the deregulated genes driving that person’s tumor. Identifying those genes would not require new technology, he said, as genomic screenings of patient tumors are already performed regularly at major cancer centers and hospitals including U.Va. Health.
Delivering the treatment past the blood-brain barrier requires a separate solution, according to the study. Unlike tumors elsewhere in the body, brain tumors sit behind that barrier, which blocks most chemotherapy drugs from reaching them. The microRNAs are packed into microscopic capsules in the lab, and are then injected into the bloodstream. To get the capsules into the tumor, the team uses focused sound waves aimed at the blood-brain barrier, according to Abounader.
“[The focused ultrasound] is used to open the blood-brain barrier at a specific place where the focused ultrasound is targeted, so that the nanoparticles … which contain the microRNAs, can penetrate into the tumor at the site where we focus the ultrasound,” Abounader said. “That’s the most important part of the delivery.”
Both microRNAs and focused ultrasound have been studied before, Abounader said, but combining them had not been tried to his knowledge.
The treatment slowed tumor growth and helped mice with glioblastoma live longer, according to the press release. However, Abounader remains cautious about the implications of the treatment for humans.
“The majority of therapies that work in mice do not work in people simply because it’s a different organism,” Abounader said. “Most of the time, it ends up not working. Sometimes it ends up working. So the more [research] we do, the greater the likelihood of us succeeding in translating this into humans.”
What stands between the research and a clinical trial is mainly financial, according to Abounader. The team needs to produce clinical-grade versions of the treatment — sterile and pure enough to be given to human patients — which takes time and funding. The sound-wave technology is already in clinical trials at U.Va. for brain tumors, he said, but it's not being used to deliver microRNAs.
With financial support, Abounader estimated trials could begin in roughly three to five years.
"We hope ... that this [experimental treatment] will lead to better therapies than the ones that we have now, which sometimes target only one molecule or none at all," Abounader said, "[We hope] that ultimately this will lead to patients surviving longer than they do now."
Vrinda Vashist is a staff writer on the news desk. She is a second-year student in the College.
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