Researchers at the University of Virginia Comprehensive Cancer Center have developed an experimental strategy that combines microRNAs, nanoparticles, focused ultrasound and microscopic bubbles to target glioblastoma. In laboratory experiments and animal models, the approach temporarily opened the blood-brain barrier, delivered genetic molecules to brain tumors, slowed tumor growth and extended survival. The method remains experimental and requires further study before it can be evaluated in human patients.
A multigene strategy for glioblastoma
A research team led by UVA’s Roger Abunader, MD, identified small genetic molecules called microRNAs that can interfere with genes involved in the development and growth of glioblastoma. The researchers packaged the microRNAs in nanoparticles and used focused ultrasound together with microscopic bubbles to help deliver them to the brain.
These technologies are designed to temporarily bypass the blood-brain barrier, a protective system that normally prevents many substances from entering the brain. That barrier can also stop potentially useful treatments from reaching brain tumors and other neurological conditions.
“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 Abu Nader, a professor in the UVA School of Medicine’s Department of Microbiology, Immunology and Cancer Biology and 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 tumor is difficult to remove completely because its cancer cells can spread into surrounding healthy brain tissue. Surgeons may therefore be unable to eliminate every cancer cell without damaging essential areas of the brain.
The blood-brain barrier presents another major obstacle. It helps protect the brain from toxins, infectious agents and other harmful substances, but it also blocks many drugs that could be used against brain tumors.
Standard 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 and extend survival. Despite these treatments, glioblastoma remains extremely difficult to manage.
Targeting multiple cancer-related genes
Rather than relying on drugs aimed at individual cancer-related processes, the UVA researchers are using microRNAs to suppress the activity of multiple genes at the same time.
This approach could slow or stop glioblastoma growth by disrupting genes that help tumor cells grow and survive. Targeting several mechanisms simultaneously may be useful 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 cross the blood-brain barrier
Delivering microRNAs into the brain is a significant challenge. To address it, Abunader’s team uses focused ultrasound guided by magnetic resonance imaging, or MRI. The imaging system allows researchers to direct the ultrasound to a specific area.
The ultrasound is used with tiny structures known as microbubbles to temporarily open the blood-brain barrier. During this brief window, nanoparticles carrying microRNAs can cross into the brain and act on genes involved in tumor growth.
The researchers evaluated the approach in laboratory experiments and animal models of glioblastoma. Their results indicated that the microRNA treatment slowed tumor growth and prolonged the animals’ survival.
The findings are promising but preliminary. Additional studies are needed to determine whether the strategy is safe and effective in human patients. Abunader said the results 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 research
UVA Health has been involved in focused ultrasound research since the technology’s early development. Its scientists have established a broad research program examining how precisely directed sound waves can be used to treat a range of medical conditions.
To investigate 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. The center is described as the world’s first facility dedicated to studying how focused ultrasound can be combined with cancer immunotherapy.
Researchers believe that combining the two approaches could lead to advances in cancer treatment during the 21st century. The work also supports the broader mission of the UVA Comprehensive Cancer Center and UVA’s Paul & Diane Manning Institute for Biotechnology, which focus on improving treatment through medical discovery.
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 institution’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 emerging treatments more accessible to patients participating in research.
Research publication and funding
Abounader and colleagues published the experimental approach and its initial results in the Journal of Clinical Investigation. The research is open access and free to read.
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 Abu Nader. 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