Each year approximately 22,000 people in the United States are diagnosed with a potentially life-threatening brain tumor. Until recently, treatment options have been limited. Glioblastoma-the most common and aggressive type of brain cancer in adults-tends to spread rapidly through the brain tissue. Because the brain is enclosed in the skull and the skull cannot expand to make room for a growing tumor, a tumor can press on or damage brain tissue. As with many tumor types, the exact cause of glioblastoma is unknown.
Glioblastoma tumors are extremely difficult to remove by surgery. Median survival for patients with glioblastoma who are treated with chemotherapy and radiation is about 14.6 months, and only about 10% of patients remain alive five years or longer after diagnosis. Thus, enrollment in a clinical trial--a last resort for patients with more treatable types of cancer--is often recommended by cancer specialists as the best treatment option.
But research supported by the Israel Cancer Research Fund (ICRF) is discovering previously unknown molecular aspects of brain cancer, providing new opportunities for diagnosis and treatment. Led by Regina Golan-Gerstl, Ph.D., a Postdoctoral Fellow in the laboratory of Rotem Karni, Ph.D. of the Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, investigators have identified a genetic protein (splicing factor hnRNP A2/B1) likely to be involved in the development and spread of glioblastoma.
The ICRF researchers analyzed tumor samples from patients with various types of brain cancer and compared them with samples taken from normal brains. They found that hnRNP A2/B1 was highly "overexpressed" (that is, higher than normal levels were detected) in the glioblastoma samples. In further studies, laboratory mice injected with glioblastoma cells quickly developed large tumors. But when investigators used a biologic technique ("knockdown") to reduce hnRNP A2/B1 before injection, the mice developed only small tumors or no tumors at all.
"These results suggest that hnRNP A2/B1 is a driving oncogene (a gene that causes normal cells to become cancerous) on its own and probably directly contributes to glioblastoma development," says Dr. Karni. "Moreover, overexpression and amplification of hnRNP A2/B1 correlate with poor prognosis of glioma patients, whereas deletion of the hnRNP A2/B1 gene correlates with better prognosis than average."
Dr. Karni and his team are also trying to identify the genes which are regulated by hnRNP A2/B1. He notes that in a previous study of brain and breast cancer cells with knockdown of hnRNP A2 "we identified key genes of very important pathways involved in cancer development and maintenance," as well as genes that indicate proliferation of cancer or tumor suppression.
"Taken together, our data suggest that hnRNP A2/B1 is a new biomarker for glioblastoma patient survival and a new proto-oncogene that regulates the splicing and other RNA processing steps of several tumor suppressors and oncogenes," says Karni. "Furthermore, downregulating hnRNP A2/B1 levels in glioblastoma cells should be considered as a new strategy for glioblastoma therapy."
Previous findings were reported in the July 1, 2011, issue of the journal Cancer Research, published by the American Association for Cancer Research.