The Hopkins team, in conjunction with researchers at the J. Craig Venter Institute in Rockville, Md., discovered DNA abnormalities in two tyrosine kinase proteins already known to disrupt normal cell activity and contribute to tumor formation.
The discovery of these mutations is especially significant, the researchers say, because tyrosine kinases can be targeted using pharmaceuticals.
"We picked these proteins to sequence because receptor tyrosine kinases sit on the cell surface where anticancer drugs can get at them," said Gregory J. Riggins, M.D., co-lead author of the study and an associate professor in the Department of Neurosurgery at The Johns Hopkins University School of Medicine.
In the study, published in the October 4th edition of The Proceedings of the National Academy of Sciences, the researchers identified two of the previously unknown mutations in fibroblast growth receptor 1 (FGFR1) and one in platelet derived growth factor receptor alpha (PDGFRA).
FGFR1 and PDGFRA, said Riggins, have been implicated in several other cancers such as colorectal, breast and ovarian cancer, as well as chronic myelogenous leukemia, gastrointestinal stromal tumors and lymphoma.
Riggins and colleagues analyzed a catalog of 518 protein kinase sequences taken from the Human Genome Project. Using high-throughput gene sequencing equipment based at the Venter Institute's Joint Technology Center, they resequenced 20 targeted proteins from tissue samples of brain tumor cells from Hopkins. The cells came from 19 glioblastoma tumors from eight females and 11 males ranging in age from 7 to 77 years. Glioblastomas are malignant tumors of the central nervous system usually found in the cortex of the brain.
Researchers discovered the mutations after comparing the resequenced genes with corresponding genes from the human genome sequence.
A previous study by Hopkins researchers, led by Victor Velculescu, M.D., Ph.D., used high-throughput gene sequencing to identify 14 mutated genes that have potential links to the growth of colon cancer cells, according to Riggins. These discoveries suggest potential future therapies that might use small molecules and antibodies to regulate the function of the mutated genes.
The success of that study prompted researchers to take the same approach to search for new drug targets for glioblastoma, a brain tumor for which current therapies are weak.
According the Riggins, the recent advances in genomic information and technology have set the stage for the assembling of a complete catalog of molecular alterations that contribute to cancers. Genes involved in the tyrosine kinase family will be important in these future studies because they play a significant role in signaling between cancer cells and what's around them. Combined with the remarkable clinical success doctors have had with the molecular targeting of this family of genes, Riggins said, these new findings could result in effective new treatments for cancer.
"The next step," he added, "is to find inhibitors of these mutations and find out how we can reverse the effects of these mutations in the cancer cell. Our hope is that we can target enough of these mutations to treat the cancer."
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