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Any seasoned soldier knows the tactical value of having the right ammunition and a well-defined target. At St. Jude Children’s Research Hospital, researchers and clinicians are wielding a formidable weapon called molecular-targeted therapy. This assault on pediatric cancer requires that they pinpoint specific targets, acquire the best ammunition and take aim to ensure direct hits.
One scientist on the front line of this war is Richard Gilbertson, MD, PhD, of St. Jude Developmental Neurobiology. As he contemplates his battle plan, Gilbertson frequently mentions how treatments have changed since the “olden days,” a scant 10 years ago, when clinicians used the same therapy to treat every child suffering from a specific type of cancer. But as St. Jude scientists learn more about the human genome and specific genetic mutations, they are finding new strategies to ambush the enemy—childhood cancer.
When using molecular-targeted therapy, researchers’ first task is to identify the target and find patients who have it.
Most anti-cancer drugs are designed to combat genetic mutations that make cells malignant. To qualify for a clinical trial based on molecular-targeted therapy, a patient cannot simply have the specific disease under study; the child must also have the specific genetic target.
“If you don’t have kids with that target in your study, then there is a great chance that they won’t respond to that drug,” Gilbertson says. “For instance, if you try a drug in patients and only a few or none of them respond, then your conclusion used to be that the drug was rubbish; it didn’t work. But that’s not necessarily the case. Perhaps it didn’t work because you didn’t put it into the right patients.”
So how do scientists identify the right patients? One option is to sequence the whole genome to look for mutations. The process is costly, laborious and time consuming. Sequencing just one gene can take a week to complete. But Gilbertson and his colleagues have discovered a quicker and less expensive way to identify children with specific targets. Using technology available in St. Jude’s Hartwell Center for Bioinformatics and Biotechnology, the researchers generated gene expression profiles of medulloblastoma tumor samples.
Gene expression profiling is a method of determining which genes are active in certain cells. The St. Jude team used a technique that looks at the expression of 18,000 genes at once in a tumor. Based on these studies, the scientists identified signatures related to the kinds of genes that were expressed. These signatures accurately predicted the presence of mutations. The researchers also discovered five distinct medulloblastoma subgroups.
“Now, if a kid walks in the door, we can complete a single test that takes half a day to do,” Gilbertson says. “We will be able to say, ‘You’ve got a mutation of this gene, and you should go into this clinical trial.’”
“What we understood 10 years ago to be medulloblastoma or ependymoma are probably four or five different diseases that just happen to look the same through the microscope. It’s understanding what those different subgroups are that matters.”
In the past, traditional chemotherapy and radiation treatments were used to kill dividing cells. But today researchers have other weapons in their arsenal, and new factors come into play. Not only does the target have to be identified, but the ammunition—the drug—has to be the right one for the job.
“You can have a very good target but a terrible drug that never gets to the target to do its job,” Gilbertson says. “Or you can have a great drug that gets to the target and does its job, but the target’s not important to the disease so the kid doesn’t respond.”
Many clinical trials now take both of these issues into account. To accelerate progress in this area, St. Jude has created the Molecular Clinical Trials Core, a central reference laboratory that helps scientists plan and execute clinical trials of molecular-targeted therapies. The facility provides its users with advice, support and molecular analyses. “It’s actually a pretty innovative venture,” says Gilbertson, the facility’s director.
The core is currently handling 10 molecular-targeted clinical trials encompassing several signaling pathways and tumor types. Samples from St. Jude and across the United States are sent to the facility. Inga Warr and Radhika Thiruvenkatam, senior research technicians, process the material and perform the necessary assays. A recent clinical trial performed in the facility clearly indicated that the drug under study worked well in a population of more than 200 patients. The findings clearly indicated that the drug inhibited its target.
“In the olden days, you would give a drug to patients and just measure whether the tumor shrank or not,” Gilbertson says. “The assumption was that if it shrank then the drug was good. That’s a no-brainer. But if the tumor didn’t shrink, the only conclusion was that the drug hadn’t worked. But you really need to know whether the drug got there and did its job. And unless you know that, you can’t fairly judge whether a drug is good or not.”
As they join forces and gain even more information about molecular-targeted therapy, St. Jude researchers and clinicians are determined to win the war against pediatric cancers.
Reprinted from Promise magazine, summer 2006.
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