APR 06, 2015 04:30 PM PDT

Cancer Genes Turned Off in Deadly Brain Cancer

Northwestern Medicine scientists have identified a small RNA molecule called miR-182 that can suppress cancer-causing genes in mice with glioblastoma mulitforme (GBM), a deadly and incurable type of brain tumor.
The molecule miR-182 is a microRNA, a type of short non-coding RNA that can bind to hundreds of genes to reduce their protein expression in cells.
While standard chemotherapy drugs damage DNA to stop cancer cells from reproducing, the new method stops the source that creates those cancer cells: genes that are overexpressing certain proteins.

"Our study identified miR-182 as a glioblastoma tumor suppressor that reduces the expression of several oncogenes that promote cancer development," said senior author of the study Alexander Stegh, an assistant professor in the Ken and Ruth Davee department of neurology and of medicine at Northwestern University Feinberg School of Medicine.

The study, published April 2 in Genes and Development, used a nanostructure called spherical nucleic acids (SNAs) to safely deliver miR-182 across the blood-brain barrier to reach tumor cells. There it directly targeted multiple oncogenes at once, increasing cancer cell death and reducing cancer cell growth. SNAs are composed of multiple strands of DNA and RNA densely arranged around a nanoparticle center.

"We demonstrate a more specific, more personalized approach to therapy," Stegh said. "SNAs are a very promising platform to silence the particular genes that drive or contribute to cancer progression in individual patients."

There are 16,000 new cases of the deadly brain tumor reported in the U.S. every year. Patients have a very poor prognosis, with median survival of just 14 to 16 months.

The molecule miR-182 is a microRNA, a type of short non-coding RNA that can bind to hundreds of genes to reduce their protein expression in cells. Looking at large-scale genomic datasets, Stegh and colleagues saw that patients with higher levels of miR-182 had a better chance of surviving glioblastoma mulitforme longer.

In the study, they found that miR-182 suppressed Bcl2L12, a cancer gene that blocks cancer cell death in response to chemo- and radiation therapy. The microRNA also impeded two other oncogenes, c-Met and HIF2A. The next challenge was establishing a way to get miR-182 to those specific targets.

The solution was in SNAs, a structure invented by Northwestern colleague and co-author Chad Mirkin, the George B. Rathmann Professor of Chemistry at the Weinberg College of Arts and Sciences and a professor of medicine at Feinberg.

"We designed a novel delivery method for miR-182 using SNAs," Stegh said. "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."

SNAs have unique properties that allow them to reach cells safely without causing toxicity or activating the immune system.

"Our approach to gene silencing has not been demonstrated before in such a powerful way for the treatment of brain cancers," Stegh said. "These particles, microRNA based SNAs, could also potentially be used for gene silencing in other cancers and diseases of genetic origin."

Additional studies will be needed to test miR-182 and the nanoparticle delivery before it becomes an option for patients with glioblastoma mulitforme. But first, Stegh and colleagues want to hone the particle design and to investigate treatments that combine miR-182 with established chemotherapy drugs in mouse models.

Source: Northwestern University
About the Author
  • Ilene Schneider is the owner of Schneider the Writer, a firm that provides communications for health care, high technology and service enterprises. Her specialties include public relations, media relations, advertising, journalistic writing, editing, grant writing and corporate creativity consulting services. Prior to starting her own business in 1985, Ilene was editor of the Cleveland edition of TV Guide, associate editor of School Product News (Penton Publishing) and senior public relations representative at Beckman Instruments, Inc. She was profiled in a book, How to Open and Operate a Home-Based Writing Business and listed in Who's Who of American Women, Who's Who in Advertising and Who's Who in Media and Communications. She was the recipient of the Women in Communications, Inc. Clarion Award in advertising. A graduate of the University of Pennsylvania, Ilene and her family have lived in Irvine, California, since 1978.
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