Scientists at the University of Virginia Comprehensive Cancer Center have developed an experimental glioblastoma treatment strategy that combines microRNAs, nanoparticles, focused ultrasound and microscopic bubbles. In laboratory and animal studies, the approach temporarily opened the blood-brain barrier, delivered genetic molecules to brain tumors and slowed tumor growth while extending survival. The researchers say the method could eventually help target multiple cancer-promoting genes at once, but further studies are needed before it can be tested in human patients.
Targeting multiple genes in glioblastoma
A research team led by Roger Abunader, MD, identified small genetic molecules called microRNAs that can interfere with genes involved in glioblastoma development and growth. To deliver the molecules to the brain, the researchers combined nanoparticles with MRI-guided focused ultrasound and microscopic bubbles.
Together, these technologies provide a way to temporarily bypass the brain’s protective barrier, which normally prevents many treatments from reaching brain tumors and other parts of the nervous system.
“This new approach could help us achieve better treatments while simultaneously targeting a large number of molecules that promote cancer growth, including those for which no therapeutic agents exist,” said Abunader, a professor in the UVA School of Medicine’s Department of Microbiology, Immunology and Cancer Biology and a member of the Comprehensive Cancer Center and Center for RNA Science and Medicine. “We hope to apply our findings to future clinical trials for patients with glioblastoma and other brain tumors.”
Why glioblastoma is difficult to treat
Glioblastoma is the most common malignant brain tumor in adults and one of the most aggressive cancers. It claims more than 13,000 lives in the United States each year. The cancer can spread into surrounding healthy brain tissue, making it nearly impossible for surgeons to remove the entire tumor.
The brain’s natural blood-brain barrier presents another major challenge. This protective system helps shield the brain from toxins, infectious agents and other harmful substances, but it also blocks many drugs that could be used to attack brain tumors.
Current treatment generally begins with surgery to remove as much of the tumor as possible. Patients then receive radiation therapy and chemotherapy to control remaining cancer cells and prolong survival. Despite these treatments, glioblastoma remains extremely difficult to manage.
Rather than relying on drugs that act on individual cancer-related processes, the UVA researchers are investigating microRNAs, which can suppress the activity of multiple genes simultaneously. By disrupting genes that help glioblastoma cells grow and survive, the treatment could potentially slow or stop tumor progression.
Targeting several mechanisms at once may be particularly important because combining multiple traditional anticancer drugs can cause harmful side effects. In addition, many molecules involved in cancer growth cannot currently be targeted with available drugs.
Using focused ultrasound to deliver microRNAs
Getting genetic molecules into the brain is a major obstacle. Abunader’s team used focused ultrasound guided by magnetic resonance imaging, or MRI, to direct sound waves precisely to the desired area.
The ultrasound was combined with tiny microbubbles to temporarily open the blood-brain barrier. This created a brief window in which nanoparticles carrying microRNAs could cross the barrier and enter the brain, where the molecules acted on genes involved in tumor growth.
The researchers tested the strategy in laboratory experiments and animal models of glioblastoma. Their findings showed that the microRNA treatment slowed tumor growth and prolonged the animals’ survival.
Although the results are promising, the strategy remains experimental and requires additional studies to determine whether it is safe and effective in human patients. Abunader said the findings provide an early indication that the technology could eventually benefit people with glioblastoma and other cancers.
“This approach has the potential to have broad applications in several brain diseases and other human diseases,” Abunader said. “We and many others are working intensively to reduce the burden of cancer and, hopefully, cure it once and for all, but this requires continued investment in cancer and medical research.”
UVA expands focused ultrasound cancer research
UVA Health has been conducting focused ultrasound research since the technology’s early development. Its scientists have built a research program investigating how precisely directed sound waves could be used to treat a range of medical conditions.
To explore the technology’s potential in cancer treatment, UVA partnered with the Charlottesville-based Focused Ultrasound Foundation to establish the Focused Ultrasound Immuno-Oncology, or FUSION, Center. It is the world’s first center dedicated to studying how focused ultrasound and cancer immunotherapy can be combined.
Researchers believe this combination could lead to advances in cancer treatment during the 21st century. The effort also supports the broader missions of the UVA Comprehensive Cancer Center and UVA’s Paul & Diane Manning Institute for Biotechnology, which work to improve treatment through medical discoveries.
The UVA Comprehensive Cancer Center is one of only 57 cancer centers nationwide to receive the National Cancer Institute’s prestigious “Comprehensive” designation. The recognition reflects the center’s cancer research and patient care programs.
The Manning Institute was established to accelerate the discovery and development of drugs and potential treatments for difficult diseases. Its work is supported by a statewide clinical trials network intended to make new treatments more accessible to patients participating in research.
Research results and support
Abunader and his colleagues published the experimental approach and initial results in the Journal of Clinical Investigation. The research is open access and available to read for free.
The research team included Shekhar Saha, Ying Zhang, Myron K. Gibert Jr., Collin Dube, Farina Hanif, Elizabeth Qian Xu Mulcahy, Sylwia Bednarek, Yunan Sun, Pawel Marcinkiewicz, Xiantao Wang, Gijung Kwak, Ahsan H. Polash, Haolin Li, Kadie Hudson, Manikarna Dinda, Tapas Saha, Matthew McCord, Fadila Guesus, Nicola Cruikshanks, Rossimar Rivera Colon, Lily Dell’Orio, Rajita Anbu, Wenjie Liu, Songji Choi, Benjamin Cefas, Pankaj Kumar, Alexander L. Klibanoff, David Schiff, Soo-seok Jeong, Justin Haynes, Jamie Mata, Marcus Hafner and Abunader. The researchers reported no financial interest in the study.
Funding came from the National Cancer Institute of the National Institutes of Health through grants U01 CA220841 and P30 CA044579, and from the NIH’s National Institute of Neurological Disorders and Stroke through grants R01 NS122222 and R21 NS122136. Additional support came from a UVA Comprehensive Cancer Center pilot grant, a Schiff Foundation grant, the Ben and Catherine Ivy Foundation and the Focused Ultrasound Foundation.
Source: www.sciencedaily.com
