Aug 29: A large group of collaborative researchers recently completed a Foundation-funded preclinical project using focused ultrasound to advance the treatment of glioblastoma. Led by Roger Abounader, MD, PhD, professor of Microbiology, Immunology, and Cancer Biology at the University of Virginia, the team tested a new therapeutic strategy that combines microRNAs, brain-penetrating nanoparticles, and focused ultrasound.
Therapeutic Delivery of microRNAs Discovered to Target Deregulated Glioblastoma Pathways Inhibits Tumor Growth in Mice
The Challenge of Treating Glioblastoma with Drugs Glioblastoma is the most common malignant primary brain tumor in adults and remains extremely difficult to treat. Standard therapies generally include surgery followed by radiation and chemotherapeutics, but glioblastoma cells infiltrate surrounding brain tissue, making complete surgical removal nearly impossible.
The biology of the disease creates another challenge. Glioblastoma is not usually driven by a single malfunctioning gene or molecular pathway. Many genes can be altered within the same tumor, and the combination of alterations can vary among patients and even among cells in one tumor.
Most molecularly targeted drugs act on one target at a time. This may allow other cancer-promoting pathways to continue supporting tumor growth. Combining several drugs could potentially address more targets, but doing so can substantially increase toxicity. Drugs also must overcome the blood-brain barrier, a protective layer of cells that prevents many substances in the bloodstream from entering the brain.
The researchers sought to develop a solution that could both target several cancer-driving genes simultaneously and deliver the treatment across the BBB.
The Therapeutic Potential of microRNAs MicroRNAs, or miRNAs, are small, naturally occurring RNA molecules that help regulate gene activity. They bind to messenger RNA (which carries instructions for making proteins) and reduce the amount of protein produced from those instructions.
A single miRNA can regulate many genes. This ability makes miRNAs particularly interesting for a complex disease such as glioblastoma, where several molecular changes may contribute to tumor growth at the same time.
Some miRNAs function as tumor suppressors, helping restrain genes that promote cancer growth. Their activity may be reduced in cancer cells. Other miRNAs can support cancer growth by suppressing genes that would normally keep tumors in check. A potential treatment could therefore restore tumor-suppressive miRNAs or inhibit cancer-promoting miRNAs.
Identifying and Delivering Promising miRNAs The research team led by Dr. Abounader combined experimental screening, data from human glioblastoma samples, and computational analysis to identify miRNAs that regulate multiple genes associated with the disease.
They chose two tumor-suppressive miRNAs, miR-340 and miR-382, along with a cancer-promoting miRNA called miR-17. In glioblastoma cell studies, restoring miR-340 or miR-382, or inhibiting miR-17, reduced cell growth and invasion. The next challenge was delivering the miRNAs to the brain tumors.
The researchers packaged DNA instructions encoding miR-340 or miR-382 inside brain-penetrating nanoparticles. They then intravenously administered these nanoparticles with microbubbles to mice with glioblastoma tumors.
The team then directed magnetic resonance imaging–guided focused ultrasound to the tumor region. The acoustic energy caused the circulating microbubbles to oscillate, temporarily opening the BBB and allowing the nanoparticles to enter the targeted brain tissue.
In two mouse models of glioblastoma, including one created from patient-derived glioblastoma stem cells, focused ultrasound–mediated delivery of both miRNAs reduced tumor burden and extended survival compared with delivery of a control sequence. Nanoparticles administered without focused ultrasound did not substantially reduce tumor burden, demonstrating the importance of focused ultrasound for successful delivery.
Why This Research Matters This study combines a potential multi-target treatment with a way to deliver it to a specific location in the brain. Instead of developing a separate drug for every altered molecule in a tumor, the miRNA approach could allow researchers to simultaneously regulate several cancer-promoting signals .
The findings also demonstrate how focused ultrasound could expand the range of therapies considered for brain tumors. Genetic medicines and other large or complex therapeutic agents often cannot cross the BBB on their own. Temporarily opening it at a selected location could help these agents reach their intended target while limiting exposure elsewhere in the brain.
The results remain preclinical. Additional research is needed to assess safety, determine appropriate dosing, evaluate repeated treatments, and establish whether the approach could work in people. Nevertheless, the study provides evidence that focused ultrasound, microbubbles, and brain-penetrating nanoparticles can work together to deliver an experimental miRNA-based therapy and alter the course of glioblastoma in animal models.
This research was funded by several grants from the National Institutes of Health, along with additional funding from the UVA Comprehensive Cancer Center, the Schiff Foundation, the Ben and Catherine Ivy Foundation, and the Focused Ultrasound Foundation.