The Role HCMV in Neural Stem Cell Oncogenesis

Malignant gliomas are extremely aggressive brain tumors that kill approximately 15,000 Americans each year within a year of diagnosis. No cause is known and no significant improvement in treatment or survival has occurred in over 40 years. In 2002, our group discovered that a common virus, cytomegalovirus (CMV) is associated with over 90% of these tumors, and recently our collaborators at Duke University have significantly improved survival in brain tumor patients by immunizing patients against CMV. Other collaborators of ours at Karolinska Institute are currently treating brain tumor patients with anti-CMV drugs in a prospective randomized trial, which will be revealed in 2009. Preliminary observations indicate that the antiviral drug may be extending these patients' lives. These exciting results imply that CMV may be a potential cause of brain tumors and that drugs against CMV might have potential as therapeutic agents for brain tumors. If this were to be the case, it would clearly be a breakthrough in our understanding and ability to treat this disease. However, little is currently known about potential mechanisms that CMV might use to cause brain tumors or promote their aggressiveness. Therefore, in order to understand whether CMV can cause brain tumors and whether blocking CMV infection might provide therapeutic benefits, we have proposed experiments that utilize biopsy-derived normal human brain cells and brain-tumor derived cells to directly answer these questions. We will obtain 'stem-like cells' from adult human brain tissues since these cells are thought to be the cells of origin of brain tumors. We will then infect these normal adult brain stem cells with CMV or engineer them to express viral gene products, after which we will analyze these cells for evidence of tumor formation. Conversely, we will use brain tumor cells from patients' tumors which are already infected with CMV and determine which CMV genes are expressed in these cells. We will then use this information to specifically block the tumor-promoting effects of CMV in glioma cells. These experiments will be used to answer the following questions: 1) Does/can CMV cause brain tumors? 2) Are certain CMV genes responsible for this? 3) Which CMV genes are expressed in human gliomas? , and 4) If we block CMV infection or genes in human brain tumor cells, can we inhibit the tumor growth? Information derived from these studies has the potential to revolutionize our understanding of brain tumor biology and therapy. Our research thus far has already led to an advance in the treatment of brain tumors as demonstrated by the increased survival in the Duke University vaccine study. We believe that further investigations along these lines can truly lead to a breakthrough for this common and lethal human malignancy.