In December 2005 the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) launched an ambitious collaboration, The Cancer Genome Atlas (TCGA), with the understanding that changes in the cellular genome (total genetic content of cells) are central to the origins of all human cancers.
An Overview of Genomic Analyses of Glioblastoma Multiforme and their Potential Research Implications
Genomic analyses have been instrumental in identifying the genes driving certain types of cancer, a key step in developing targeted drug therapies. For example, genomic analyses have identified the Her2 gene as driving aggressive metastatic breast cancer in some patients, which has led to the development of Herceptin as a therapy for treating patients. However, genomic analysis of brain tumors has lagged behind that of other cancers.
In December 2005 the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) launched an ambitious collaboration, The Cancer Genome Atlas (TCGA), with the understanding that changes in the cellular genome (total genetic content of cells) are central to the origins of all human cancers. As a first step, TCGA launched a pilot program to systematically analyze genomic changes in three cancer/tumor types, including glioblastoma multiforme (GBM).
The first interim GBM genomic analysis results were published in the journal Nature (September 2008). The comprehensive TCGA results solidified the importance of three core cell signaling pathways involved in GBM and provided an unparalleled overview of the highly interconnected network of pathway aberrations. In three-quarters of GBM tumors, all three of these pathways show mutations. In addition, mutations within three genes not previously recognized as important in GBMs were found with significant frequency, and these genes define new potential interventional targets.
The study also demonstrated that while chemotherapy (temozolomide) for GBM under certain genomic conditions (MGMT gene methylation) effectively extends the life of GBM patients, it is also responsible for causing an increase of mutations in surviving GBM cells. This is important because the more mutations that occur in the tumor cells that remain after chemotherapy, the more likely it is that recurrent tumors will become resistant to subsequent treatment.
A second important parallel GBM genomic analysis by researchers at The Johns Hopkins Kimmel Cancer Center, published at the same time, provided similar results and identified an additional gene mutation in a significant number of GBM tumors.
While it would have been a lot simpler if the genomic analyses pointed out a single aberration that if targeted would kill GBM cells, these analyses have provided a much greater and more sophisticated understanding of the complex challenges of GBM development, which can be influenced by multiple pathways. These exciting analyses explain why attempts to treat GBM using drugs that target only one or even two components of the signal transduction pathways that drive the tumors have been largely unsuccessful. The highly complex interactions between pathways suggests that specific critical pathway intersection points may need to be targeted in order to effectively shut down the offending pathways sufficiently to kill the tumor cells. This approach provides special promise to lead to the identification of effective combinations of drugs within the dizzyingly enormous array of potential combination of drugs that target the GBM pathways.
NBTS sees comprehensive genomic analyses (as well as the broader molecular profiling of such things as the protein products of genes) as critical to transforming research in both adult and pediatric brain tumors. Our belief in this is reflected in our new pediatric brain tumor research initiative. We are currently inviting pediatric tumor experts to submit research applications for comprehensive molecular profiling of pediatric brain tumors because we are lacking this information now. NBTS is committed to assisting academia and industry to continue this critical work toward a therapeutic solution for all brain tumors.