Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor that affects humans. To date there are very few treatment options and overall patient prognosis is poor. However, recent findings from researchers at Northwestern Medical School look at a new treatment option that has the potential to dramatically change the outcome of patients afflicted with this form of brain cancer.
The findings from this study were published recently in Genes & Development through an article entitled “miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma.”
The traditional standard of care for GBM has been targeted radiation and chemotherapeutic drugs, which are designed to damage DNA in rapidly dividing cancer cells, preventing them from further proliferation. The current study looks to deliver a microRNA molecule to target genes that are overexpressing proteins thought to play a major role in tumor progression.
“Our study identified miR-182 as a glioblastoma tumor suppressor that reduces the expression of several oncogenes that promote cancer development,” said Alexander Stegh, Ph.D., assistant professor of neurology at Northwestern University Feinberg School of Medicine and senior author on the current study.
Dr. Stegh and his team developed a nanostructure delivery vehicle, called spherical nucleic acids (SNAs), that could traverse the blood-brain barrier to deliver the miR-182 microRNA molecule to the tumor cells. Once miR-182 gained access to the cell it was able to downregulate several oncogenes involved in tumor development.
“We demonstrate a more specific, more personalized approach to therapy,” stated Dr. Stegh. “SNAs are a very promising platform to silence the particular genes that drive or contribute to cancer progression in individual patients.”
After looking at large amounts of genomic data, Dr. Stegh and his team noticed that GBM patients with higher levels of miR-182 had increased survival rates. In the laboratory, investigators found that miR-182 suppressed the Bcl2L12 gene, which has been shown to prevent apoptosis of cancer cells in response to treatment from chemo- and radiation therapy. Moreover, miR-182 was able to block two other oncogenes shown to have a role in GBM, c-Met, and HIF2A.
Since targeting the microRNA molecule to the proper cells is critical, the creation of the SNAs as a delivery vehicle is no less of an important discovery than the antitumor activity Dr. Stegh and his colleagues observed for miR-182. SNAs are composed of multiple strands DNA and RNA of densely arranged around a nanoparticle core that were easily able to cross the blood-brain barrier
“We designed a novel delivery method for miR-182 using SNAs,” explained Dr. Stegh. “Small gold nanoparticles are conjugated with miR-182 sequences. They cross the blood-brain/blood-tumor barrier, and accumulate within brain tumor sites, where they target oncogenes, regulate cell growth and differentiation, reduce tumor burden, and prolong survival in our mouse models.”
The Northwestern researchers are optimistic that their novel approach will lead to better outcomes for patients suffering from GBM, but they concede that additional studies will be needed to further test the efficacy and safety of miR-182 and SNAs.
“Our approach to gene silencing has not been demonstrated before in such a powerful way for the treatment of brain cancers,” concluded Dr. Stegh.”These particles, microRNA based SNAs, could also potentially be used for gene silencing in other cancers and diseases of genetic origin.”