Hopkins Geneticist Discovers Mutations In Cancer Cells That Suggest New Forms Of Treatment

The Hopkins team, in conjunction with researchers at the J. CraigVenter Institute in Rockville, Md., discovered DNA abnormalities in twotyrosine kinase proteins already known to disrupt normal cell activityand contribute to tumor formation.

The discovery of these mutations is especially significant, theresearchers say, because tyrosine kinases can be targeted usingpharmaceuticals.

"We picked these proteins to sequence because receptor tyrosinekinases sit on the cell surface where anticancer drugs can get atthem," said Gregory J. Riggins, M.D., co-lead author of the study andan associate professor in the Department of Neurosurgery at The JohnsHopkins University School of Medicine.

In the study, published in the October 4th edition of TheProceedings of the National Academy of Sciences, the researchersidentified two of the previously unknown mutations in fibroblast growthreceptor 1 (FGFR1) and one in platelet derived growth factor receptoralpha (PDGFRA).

FGFR1 and PDGFRA, said Riggins, have been implicated in severalother cancers such as colorectal, breast and ovarian cancer, as well aschronic myelogenous leukemia, gastrointestinal stromal tumors andlymphoma.

Riggins and colleagues analyzed a catalog of 518 protein kinasesequences taken from the Human Genome Project. Using high-throughputgene sequencing equipment based at the Venter Institute's JointTechnology Center, they resequenced 20 targeted proteins from tissuesamples of brain tumor cells from Hopkins. The cells came from 19glioblastoma tumors from eight females and 11 males ranging in age from7 to 77 years. Glioblastomas are malignant tumors of the centralnervous system usually found in the cortex of the brain.

Researchers discovered the mutations after comparing theresequenced genes with corresponding genes from the human genomesequence.

A previous study by Hopkins researchers, led by VictorVelculescu, M.D., Ph.D., used high-throughput gene sequencing toidentify 14 mutated genes that have potential links to the growth ofcolon cancer cells, according to Riggins. These discoveries suggestpotential future therapies that might use small molecules andantibodies to regulate the function of the mutated genes.

The success of that study prompted researchers to take thesame approach to search for new drug targets for glioblastoma, a braintumor for which current therapies are weak.

According the Riggins, the recent advances in genomicinformation and technology have set the stage for the assembling of acomplete catalog of molecular alterations that contribute to cancers.Genes involved in the tyrosine kinase family will be important in thesefuture studies because they play a significant role in signalingbetween cancer cells and what's around them. Combined with theremarkable clinical success doctors have had with the moleculartargeting of this family of genes, Riggins said, these new findingscould result in effective new treatments for cancer.

"The next step," he added, "is to find inhibitors of thesemutations and find out how we can reverse the effects of thesemutations in the cancer cell. Our hope is that we can target enough ofthese mutations to treat the cancer."