An international research team reports in Nature Medicine a novel molecular pathway that causes an aggressive form of medulloblastoma, and suggests repurposing an anti-depressant medication to target the new pathway may help combat one of the most common brain cancers in children.
The multi-institutional group, led by scientists at Cancer and Blood Diseases Institute (CBDI) at Cincinnati Children's Hospital Medical Center, publish their results in the journal's online edition on Aug. 24. The researchers suggest their laboratory findings in mouse models of the disease could lead to a more targeted and effective molecular therapy that would also reduce the harmful side effects of current treatments, which include chemotherapy, radiation or surgery.
"Although current treatments improve survival rates, patients suffer severe side effects and relapse tumors carry mutations that resist treatment," said lead investigator Q. Richard Lu, PhD, scientific director of the Brain Tumor Center, part of the CBDI at Cincinnati Children's. "This underscores an urgent need for alternative targeted therapies, and we have identified a potent tumor suppressor that could help a subset of patients with an aggressive form of medulloblastoma."
Using genetically-engineered mice to model human medulloblastoma, the authors identified a gene called GNAS that encodes a protein called Gsa. Gsa kicks off a signaling cascade that researchers found suppresses the initiation of an aggressive form of medulloblastoma driven by a protein called Sonic hedgehog – considered one of the most important molecules in tissue formation and development.
The scientists used an anti-depressant medication called Rolipram – approved for behavioral therapy for use in Europe and Japan – to treat mice that were engineered not to express the GNAS gene. Lack of GNAS allowed aggressive formation of medulloblastoma tumors in neural progenitor cells of the GNAS mutant mice.
Rolipram treatment in the mice elevated levels of a molecule called cAMP, which restored the GNAS-Gsa pathway's tumor suppression function. This caused the tumors to shrink and subside. The study also suggests that elevating cAMP levels in cells enhances the potency of Sonic hedgehog inhibitors, currently being tested in clinical trials to fight tumor growth.
The scientists stressed that a significant amount of additional research is needed before their findings could become directly relevant to clinical treatment. The authors also caution that the effect of raising cAMP levels may depend on the type of cancer, and that laboratory results in mice do not always translate uniformly to humans.
Collaborating on the study with Dr. Lu was first author, Xuelian He (MD, a postdoctoral fellow), of the CBDI at Cincinnati Children's and the West China Second Hospital, Sichuan University, in Chengdu, China.
Other collaborating institutions include: The Hospital for Sick Children, University of Toronto, Toronto; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea; the German Cancer Research Center, Heidelberg, Germany; the National Institute of Diabetes and Digestive and Kidney Diseases (NIH); Department of Neurology, Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston; St. Jude Children's Research Hospital, Memphis; departments of Pediatrics, Anatomy and Neurobiology, Washington University School of Medicine, St Louis; Tumor Development Program, Sanford-Burnham Medical Research Institute, La Jolla, Calif.
Funding support came in part from the National Institutes of Health (R01NS078092, R01NS075243) and the Canadian Institutes of Health Research.
About Cincinnati Children's:
Cincinnati Children's Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in U.S. News and World Report's 2014 Best Children's Hospitals. It is also ranked in the top 10 for all 10 pediatric specialties. Cincinnati Children's, a non-profit organization, is one of the top three recipients of pediatric research grants from the National Institutes of Health, and a research and teaching affiliate of the University of Cincinnati College of Medicine. The medical center is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. Additional information can be found at http://www.cincinnatichildrens.org. Connect on the Cincinnati Children's blog, via Facebook and on Twitter.
Nick Miller | Eurek Alert!
Study suggests new way of preventing diabetes-associated blindness
26.05.2015 | Johns Hopkins Medicine
Memories Influence Choice of Food
22.05.2015 | Universität Basel
The only professorship in Germany to date, one master's programme, one laboratory with worldwide unique equipment and the corresponding research results: The University of Würzburg is leading in the field of biofabrication.
Paul Dalton is presently the only professor of biofabrication in Germany. About a year ago, the Australian researcher relocated to the Würzburg department for...
Physicists have developed an innovative method that could enable the efficient use of nanocomponents in electronic circuits. To achieve this, they have developed a layout in which a nanocomponent is connected to two electrical conductors, which uncouple the electrical signal in a highly efficient manner. The scientists at the Department of Physics and the Swiss Nanoscience Institute at the University of Basel have published their results in the scientific journal “Nature Communications” together with their colleagues from ETH Zurich.
Electronic components are becoming smaller and smaller. Components measuring just a few nanometers – the size of around ten atoms – are already being produced...
Development and implementation of an advanced automobile parking navigation platform for parking services
To fulfill the requirements of the industry, PolyU researchers developed the Advanced Automobile Parking Navigation Platform, which includes smart devices,...
The world's first electrical car and passenger ferry powered by batteries has entered service in Norway. The ferry only uses 150 kWh per route, which...
On Tuesday, 19 May 2015 the research icebreaker Polarstern will leave its home port in Bremerhaven, setting a course for the Arctic. Led by Dr Ilka Peeken from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) a team of 53 researchers from 11 countries will investigate the effects of climate change in the Arctic, from the surface ice floes down to the seafloor.
RV Polarstern will enter the sea-ice zone north of Spitsbergen. Covering two shallow regions on their way to deeper waters, the scientists on board will focus...
20.05.2015 | Event News
18.05.2015 | Event News
12.05.2015 | Event News
27.05.2015 | Power and Electrical Engineering
27.05.2015 | Health and Medicine
27.05.2015 | Physics and Astronomy