Scientists develop technique to target brain tumour growth
linked to cancer mutations could easily be identified aiding
predictions as to which patient will respond favourably to novel
drug treatments.
The 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 signalling pathways that are abnormally activated. Such treatments could not only save lives but also eliminate the severe side effects caused by current therapies.
The new method is set to particularly benefit children who often undergo chemotherapy that is unpredictable and dangerous to the individual. The technique aims to reduce this by locating specific pathways in cancer that might be vulnerable to novel therapies, speeding development of so-called molecular-targeted therapies for a wide variety of cancers.
Investigators at St. Jude Children's Research Hospital believe that the ability to determine in individual children which biochemical signalling 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 signalling 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.
Medulloblastoma was specifically targeted as they arise in the back of the brain and account for about 20 per cent of childhood brain tumours.
"Our strategy would ensure that a new drug would get a fair trial by using it to treat only the appropriate children," said Richard Gilbertson, senior author of the study's paper.
"That will be important as novel drugs are developed to treat medulloblastoma."
The St. Jude team used a unique approach for identifying the signalling pathways that cause medulloblastoma in different groups of children.
"The medulloblastoma cell is composed of proteins making up the specific signalling pathway that is abnormally activated by a gene mutation," he said.
"The group of genes in question causes the pathway to become 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 tumours by studying which genes are expressed by those tumours.
Since a specific pathway regulates each of these gene expression signatures, these genes essentially report to us which pathway might be causing the cancer. Using this information, researchers can use drugs to block that pathway.
The 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, 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 tumours.
"The current solution to that problem--to identify the DNA sequence of all the genes in each child's tumour to determine which ones are mutated--is an enormous and expensive undertaking," Gilbertson commented.
