Johns Hopkins Medicine
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Sept. 26, 2005


Researchers at Johns Hopkins and J. Craig Venter Institute in Rockville, Md., helped identify three new genetic mutations in brain tumors, a discovery that could pave the way for more effective cancer treatments.

The researchers 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, 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.

Hopkins researchers chose cells from 19 glioblastoma tumor samples 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. The cells were sent to Venter Institute’s Joint Technology Center, where researchers led by co-author Robert L. Strausberg, Ph.D. used high-throughput gene sequencing equipment to resequence 20 targeted proteins.

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 to 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.”

Funding for this study was provided by Ludwig Trust, the Children’s Cancer Foundation, the Irving J. Sherman Research Professorship and J. Craig Venter Science Foundation.

Authors on this paper are Riggins, Vikki Rand, Jennifer B. Edwards, Charles Eberhart and Kathleen M. Murphy of Hopkins; Strausberg, J. Craig Venter, Jiaqi Huang, Tim Stockwell, Steve Ferriera, Samuel Levy, Dana Busam, Kelvin Li, Alexia Tsiamouri, Karen Beeson of Venter; Oleksander Buzko of the San Diego Supercomputer Center, La Jolla, Calif., and Andrew J. G. Simpson of the Ludwig Institute for Cancer Research, New York, N.Y.