Investigators at St. Jude Children’s Research Hospital have developed a strategy to speed future development of more effective and less toxic treatments for medulloblastoma, a type of brain cancer. Medulloblastomas arise in the back of the brain and account for about 20 percent of childhood brain tumors.
The new technique could also be used to identify specific pathways in other types of cancer that might be vulnerable to novel therapies, and therefore speed development of so-called molecular-targeted therapies for a wide variety of cancers. Molecular-targeted therapies work by blocking individual molecules that are key triggers of disease.
This St. Jude study is important because the aggressive combination of surgery, radiation and chemotherapy used to treat medulloblastoma fails to cure many patients, according to researchers. Therefore, there is a great need to identify alternative therapies, such as novel drugs that block signaling pathways that are abnormally activated. Such treatments could not only save lives but also eliminate the severe side effects caused by current therapies, according to Richard Gilbertson, M.D., Ph.D., an associate member of the Department of Developmental Neurobiology at St. Jude and director of the Molecular Clinical Trials Core. Gilbertson, co-director of the St. Jude Neurobiology and Brain Tumor Program, is senior author of a paper on this work that appears in the April issue of Journal of Clinical Oncology.
The technique is designed to rapidly match a specific novel drug treatment to those children most likely to respond to it. This approach would avoid trial-and-error therapy that fails in patients who are not ideal candidates for a specific treatment, researchers said. It would also reduce the chance that otherwise effective drugs would be abandoned because they failed in such patients during clinical trials.
The key to the new St. Jude strategy is the ability to determine in individual children which biochemical signaling pathway triggers and sustains the cancer by identifying key genes that are linked to that pathway. The investigators proved that this strategy is valid by demonstrating that it is possible to assign children with medulloblastoma into specific groups, depending on which biochemical signaling pathway is abnormally active. Based on this classification, novel drugs designed to block a key protein in each specific pathway could be correctly administered to the children most likely to respond to them.
"Our strategy would ensure that a new drug would get a fair trial by using it to treat only the appropriate children," Gilbertson said. "That will be important as novel drugs are developed to treat medulloblastoma."
St. Jude researchers reported in the September 2004 issue of Cancer Cell that a novel drug called ShhAntag effectively targets such a pathway in mice with medulloblastoma and dramatically reduces the size of the tumor.
The St. Jude strategy overcomes two problems that often pose barriers to molecular targeted therapies. First, not all children have the same gene mutations that cause a specific cancer, Gilbertson said, so a novel therapy that targets only a gene known to cause the cancer in one group of children will not be effective in a child whose same cancer is caused by a different mutation. Secondly, scientists have identified only a few genes that are potential targets for novel drugs in medulloblastomas, and even fewer in other brain tumors. The current solution to that problem—to identify the DNA sequence of all the genes in each child’s tumor to determine which ones are mutated—is an enormous and expensive undertaking, he said.
However, the St. Jude team used an approach for identifying the signaling pathways that cause medulloblastoma in different groups of children.
"Our strategy is somewhat analogous to the link between a home’s electrical wiring system and a light bulb," Gilbertson said. "You know if a certain part of the wiring network is working if the light bulb connected to it is on. In the medulloblastoma cell, the wiring is composed of proteins making up the specific signaling pathway that is abnormally activated by a gene mutation, and the light bulb is the group of genes that the pathway causes to be over-expressed."
The St. Jude team showed in samples of medulloblastoma from different groups of children that it is possible to determine which gene mutations are present in tumors by studying which genes are expressed by those tumors.
"Since each of these gene expression signatures is regulated by a specific pathway, these genes essentially report to us which pathway might be causing the cancer," Gilbertson said. "Using this information, researchers can use drugs to block that pathway."