Tumor Mutations May Lead to New Therapy

The researchers, from Johns Hopkins University (Baltimore, MD, USA), working with scientists at the J. Craig Venter Institute (Rockville, MD, USA) identified DNA abnormalities in two tyrosine kinase proteins already known to disrupt normal cell activity and contribute to tumor formation. The findings of these mutations is particularly significant, according to the researchers, because tyrosine kinases can be targeted using pharmaceutical agents.

"We picked these proteins to sequence because receptor tyrosine kinases sit on the cell surface where anticancer drugs can get at them,” stated 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 4, 2005, issue of the journal The Proceedings of the [U.S.] National Academy of Sciences, the investigators 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, according to Dr. Riggins, have been implicated in several other cancers such as colorectal, ovarian, and breast cancer, as well as chronic myelogenous leukemia, lymphoma, and gastrointestinal stromal tumors. Dr. Riggins and coworkers studied a catalog of 518 protein kinase sequences taken from the Human Genome Project. Using high-throughput gene-sequencing technology based at the Venter Institute's Joint Technology Center, they resequenced 20 targeted proteins from tissue samples of brain tumor cells from Johns Hopkins. The cells came from 19 glioblastoma tumors from eight females and 11 males ranging in age from 7-77 years. Glioblastomas are malignant tumors of the central nervous system typically found in the cortex of the brain.

The scientists identified the mutations after comparing the resequenced genes with corresponding genes from the human genome sequence. An earlier 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 Dr. Riggins. These findings suggest possible future therapies that might utilize 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 inadequate. According the Dr. Riggins, the recent developments in genomic information and technology have set the stage for the gathering of a complete catalog of molecular alterations that contribute to cancers. Genes involved in the tyrosine kinase family will be significant in these future studies because they play an important role in signaling between cancer cells and what is surroundings them. Combined with the extraordinary clinical success clinicians have had with the molecular targeting of this family of genes, according to Dr. Riggins, these new discoveries 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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