A new study is giving researchers hope that novel targeted therapies can be developed for glioblastoma multiforme (GBM), the most common and most aggressive form of brain cancer, after demonstrating for the first time that a gene known as melanoma differentiation associated gene-9/syntenin (mda-9/syntenin) is a driving force behind the disease's aggressive and invasive nature.
Recently published in the journal Neuro-Oncology, the study led by Virginia Commonwealth University Massey Cancer Center and VCU Institute of Molecular Medicine (VIMM) researchers used cell cultures and animal models to uncover the mechanisms by which mda-9/syntenin causes GBM to grow and invade normal brain tissue. Additionally, by using publicly available cancer genomic database information (bioinformatics) and analyzing tissue samples from patients with GBM, the researchers found that increased levels of mda-9/syntenin correlated with more advanced tumors and shorter survival. The study's discoveries pinpoint molecular targets that could be used to develop new therapies, and also suggest that the gene could be used to help stage and monitor this aggressive disease.
"Our current study represents a major breakthrough in understanding what drives GBM, and it is a starting point for the development of future therapies," says the study's lead author Paul B. Fisher, M.Ph., Ph.D., Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics research program at VCU Massey Cancer Center, chairman of the Department of Human and Molecular Genetics at VCU School of Medicine and director of the VIMM. "Because mda-9/syntenin is expressed more in advanced disease, we are also hopeful that we may be able to use the gene to monitor for disease progression and test whether certain therapies are working."
Mda-9/syntenin was originally discovered by Fisher, and through bioinformatics he has found that the gene is overexpressed in a majority of cancers. He and his colleagues also found that mda-9/syntenin interacts with a predicted 151 cancer-related proteins through its PDZ domains, which are chains of amino acids that enable cell signaling by facilitating interactions between proteins.
In GBM, Fisher and his colleagues demonstrated that overexpression of mda-9/syntenin enhanced the cells' ability to invade healthy tissue. In contrast, blocking expression of mda-9/syntenin in animal models reduced invasion, suppressed cell migration and caused tumors to shrink. Additionally, blocking the expression of mda-9/syntenin decreased the production and secretion of interleukin 8 (IL-8) proteins, which are signaling proteins that contribute to tumor growth and progression by promoting cell migration and the development of new blood vessels, a process known as angiogenesis.
"We are now focusing on developing small molecules, or drugs, that block the binding of specific cancer-promoting proteins that interact with mda-9/syntenin through its PDZ domains," says Fisher. "If successful, these PDZ-targeted therapies could potentially lead to effective treatments for GBM."
Fisher collaborated on this research with Timothy P. Kegelman, graduate student in the M.D./Ph.D. program at VCU School of Medicine; Manny Bacolod, Ph.D., instructor in the Department of Human and Molecular Genetics at VCU School of Medicine; Bin Hu, Ph.D., postdoctoral researcher in the VCU Department of Human and Molecular Genetics; Devanand Sarkar, M.B.B.S., Ph.D., Harrison Research Scholar and member of the Cancer Molecular Genetics research program at VCU Massey, associate professor in the VCU Department of Human and Molecular Genetics and associate scientific director of cancer therapeutics at VIMM; Swadesh K. Das, Ph.D., instructor in the VCU Department of Human and Molecular Genetics and VIMM member; Luni Emdad, M.B.B.S., Ph.D., member of the Cancer Molecular Genetics research program at VCU Massey, assistant professor in the VCU Department of Human and Molecular Genetics and VIMM member; Santanu Dasgupta, Ph.D., member of the Cancer Molecular Genetics research program at VCU Massey, assistant professor in the VCU Department of Human and Molecular Genetics and VIMM member; Mitchell E. Menezes, Ph.D., postdoctoral research scientist in the VCU Department of Human and Molecular Genetics; Christine E. Fuller, M.D., professor and director of neuropathology in the Department of Pathology at VCU School of Medicine; Paul Dent, Ph.D., Universal Corporation Distinguished Professor for Cancer Cell Signaling and member of the Developmental Therapeutics research program at VCU Massey and professor and chair of research in the Department of Neurosurgery at VCU School of Medicine; Albert S. Baldwin, Ph.D., professor at the University of North Carolina; Jeffrey N. Bruce, M.D., professor and vice-chair at Columbia University; and Maurizio Pellecchia, Ph.D., professor at Sanford-Burnham Medical Research Institute.
This study was supported by National Institutes of Health grant R01 CA134721, the National Foundation for Cancer Research, Goldhirsh Foundation for Brain Tumor Research, the Dana Foundation and, in part, by VCU Massey Cancer Center's NIH-NCI Cancer Center Support Grant P30 CA016059.
The full manuscript of this study is available online at: http://neuro-oncology.oxfordjournals.org/content/early/2013/12/03/neuonc.not157.full?keytype=ref&ijkey=7bky3mv0fplTyPb
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About VCU Massey Cancer Center
VCU Massey Cancer Center is one of only 68 National Cancer Institute-designated institutions in the country that leads and shapes America's cancer research efforts. Working with all kinds of cancers, the Center conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It offers the most cancer clinical trials in Virginia and serves patients at 10 locations. Its 1,000 researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately to cure cancer. Visit Massey online at http://www.massey.vcu.edu or call 877-4-MASSEY for more information.
About VCU and the VCU Medical Center
Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU's 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation's leading academic medical centers. For more, see http://www.vcu.edu.
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