New approaches in treating kids with brain tumors
MEMPHIS, Tenn. — Doctors noticed long ago that although children afflicted with the most common type of malignant brain tumor were getting the same treatment, the outcomes differed greatly, with some kids being cured completely while others died.
“We just didn't know how or why,” said Dr. Richard Gilbertson, director of the comprehensive cancer center at St. Jude Children's Research Hospital.
But the Pediatric Cancer Genome Project launched by St. Jude and Washington University in St. Louis is yielding vital new insights about how medulloblastoma develops — and how doctors might be able to cure more cases of it, researchers said.
The genome project — a three-year, $65 million effort to discover the genetic changes that lie at the root of deadly childhood cancers — allowed researchers to trace the brain tumors to previously unknown mutations involving genes that can be regulated through existing medication.
“It's possible that we can quite rapidly look at these drugs as therapies for these particular patient subgroups,” Gilbertson said.
Gilbertson and another St. Jude researcher, Jinghui Zhang, an associate member of the hospital's department of computational biology, were the corresponding authors of a study published in the scientific journal Nature.
The findings on medulloblastoma are only the latest fruits of the genome project. Previous studies generated by the project identified new approaches for treating eye tumors and a particularly aggressive form of leukemia, while another traced the genetic alterations leading to a rare and usually fatal type of brain tumor.
“I think the project has been a greater success than we could have ever imagined,” said Dr. Jim Downing, scientific director at St. Jude.
The focus of the latest study, medulloblastoma, has a relatively grim record, with little progress reported in recent decades on developing drugs to treat it.
While the long-term survival rate for all types of childhood cancer has risen to about 80 percent, medulloblastoma still kills 25 percent to 30 percent of patients within five years of diagnosis. And many of those who survive are plagued with lifelong cognitive problems and other ill effects from radiation treatment.
Through the genome project, researchers were able to sequence the complete normal and cancer genomes of 37 young patients with medulloblastoma. They then checked tumors from an additional 56 patients for the same mutations.
That allowed the scientists to identify the genetic missteps driving three of the four subtypes of medulloblastoma, including the deadliest one.
In that subtype — for which the three-year survival rate is only 60 percent — researchers discovered a series of mutations causing one gene to continually instruct cells to divide while deactivating another gene that otherwise would halt the process.
“What we found is, there are multiple mutations working together to keep cells in an immature, proliferating state, which is exactly what a brain tumor is — a collection of unruly cells that don't know when to stop dividing,” Gilbertson said.
The most promising aspect of the finding, Gilbertson said, is that the main gene instigating the cell proliferation already is the target of drugs developed to treat some adult cancers.
The same is true of three genes implicated in the development and spread of the least-dangerous subtype of medulloblastoma. As a result, researchers say, existing drugs offer hope of a safer way of treating the subtype.
Launched in January 2010, the genome project involves decoding the genomes of more than 600 cancer patients who have donated tumor and healthy-tissue samples.
Through the project, St. Jude and Washington University recently were able to announce the largest-ever release of comprehensive human cancer genome data for free access by the global scientific community.