January 25, 2011 • Volume 8 / Number 2
Seeking Better Treatments for Brain Tumors in Children
Minimizing the harmful side effects from cancer treatments is always important, and particularly so when treating brain tumors in children. Doctors can cure most cases of medulloblastoma, the most common malignant brain tumor in children, but radiation and chemotherapy can cause cognitive deficits in young survivors and lead to health problems later in life.
To find new treatments and to improve the care of all patients, researchers are using DNA sequencing and other new approaches to characterize tumors. The goals are to better classify patients according to the underlying biology of their tumors and to develop new treatments based on this information.
“As clinicians, we’re all trying to come up with smarter ways to treat patients with medulloblastoma, both because we just can’t cure some patients and because therapy can be hard on developing brains,” said Dr. Will Parsons of Texas Children’s Cancer Center and Baylor College of Medicine, who was the first author of a genetic study of medulloblastoma published last month in Science.
That report and two others, also published last month, provided insights into the genetic and cellular origins of the disease. The study published in Science surveyed the “genetic landscape” of medulloblastoma, while the other reports (here and here) described the molecular subtypes of the disease and introduced new tools for studying these tumors.
“These three studies are at the forefront of a large body of genomics-based research that, in the next few years, will redefine how medulloblastoma is diagnosed and how new treatments for patients with medulloblastoma are developed,” said Dr. Malcolm Smith of NCI’s Cancer Therapy Evaluation Program (CTEP), who was not involved in the research.
Doctors have long known that medulloblastoma is a heterogeneous disease. Some tumors are cured relatively easily, whereas others, particularly those that represent recurrences, resist treatment. The reasons for this variation are not fully understood, but genetic studies have suggested that medulloblastoma consists of at least four subtypes, each with distinct genetic and clinical features.
Profiling a Pediatric Tumor
“If we could figure out which kids we could safely give less therapy to without affecting their outcomes, that would be a really important step,” said Dr. Parsons. “When we give radiation to children who are 2 or 3 or 4 years old, it can potentially cause significant health problems.”
In the genetic study, Dr. Victor Velculescu of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and his colleagues surveyed the genetic alterations and changes in the number of gene copies in 22 tumors from patients with medulloblastoma. The researchers used similar methods as in their previous genetic studies of adult cancers, including breast, colon, and glioblastoma, the most common brain tumor in adults. (Last week, the team published a report that profiled pancreatic neuroendocrine tumors.)
Perhaps the study’s most striking result was that fewer genetic mutations were found in this childhood cancer than have been found in adult cancers. On average, medulloblastoma tumors had 11 genetic mutations, of which one or more may play a role in cancer, compared with between 50 and 100 mutations in the adult cancers studied to date, the researchers reported.
“We think that a smaller number of genetic alterations is likely to be a general feature of all pediatric cancers,” said Dr. Velculescu. In theory, he continued, having fewer mutations in tumors could help investigators focus on the critical changes in the disease by narrowing the set of possible alterations.
Epigenetic Changes in Cancer
The genetic study, which NCI funded, confirmed the presence and general frequency of previously known mutations in medulloblastoma, such as those in the Wnt and hedgehog signaling pathways. But the researchers also discovered that some tumors harbored previously unknown mutations in the genes MLL2 and MLL3. These genes are involved in histone methylation, an epigenetic process that affects the structure of chromatin and the regulation of other genes.
Although the role of these mutations in medulloblastoma is not yet known, the discovery follows recent reports in other cancers of mutations in genes that are associated with epigenetic processes. “The new findings, when considered with other recent studies, suggest that epigenetic modifications are going to be an important pathway in cancer,” said Dr. Daniela Gerhard, who directs NCI’s Office of Cancer Genomics and is a co-author of the Science study.
“But the data are just coming in, so we need to determine the importance of these changes,” she continued. It is not known, for instance, whether epigenetic changes are a driver of the disease, or whether these changes are important in the survival of tumors. Dr. Gerhard also cautioned that the study was merely a first look at the genome, and “there are still quite a lot of genetic alterations to be discovered in medulloblastoma.”
Four Distinct Subtypes
In the second study, Dr. Michael Taylor of the Hospital for Sick Children, in Toronto, and his colleagues identified four distinct subgroups of medulloblastoma based on an analysis of gene expression and DNA copy number changes in more than 100 tumors. The subgroups included patients who had distinct demographics, clinical presentations, and outcomes, and whose tumors had distinct genetic signatures and abnormalities. The findings appeared in the Journal of Clinical Oncology (JCO).
Dr. Smith noted that the subtypes identified in the JCO study are supported by results from other researchers. Because the subtypes were associated with distinct patient outcomes, he continued, doctors could potentially use the subtypes in the future to help guide decisions about treatment. For instance, patients with a particularly aggressive subtype could receive more therapy, and patients who are likely to respond to initial therapy could be spared unnecessary treatment.
Unexpected Cellular Origins
The third study identified a different cell of origin for one of the medulloblastoma subtypes. Previous studies have suggested that medulloblastoma tumors originate in the cerebellum, where the tumors are located. But Dr. Richard Gilbertson of the St. Jude Children’s Research Hospital and his colleagues found that tumors associated with changes in the Wnt pathway arise from the dorsal brainstem rather than the cerebellum.
“We had a hypothesis that the cell of origin might be different, but the fact that the cell of origin wasn’t even in the cerebellum was remarkable,” Dr. Gilbertson said. The findings, he noted, “truly show that [different] subtypes of medulloblastoma are intrinsically different diseases.”
Writing in Nature, the researchers concluded that different treatments will be required for these diseases. As part of the study, the team developed mouse models that can be used to further investigate the biology of these tumors.
Testing a Targeted Therapy
Insights into the biology of medulloblastoma tumors have already led to a clinical trial testing a targeted therapy in this disease. An experimental drug called GDC-0449, which inhibits the hedgehog signaling pathway, is being evaluated in children with recurrent medulloblastoma. Last summer, researchers reported that the drug was safe and well tolerated in a phase I trial involving about a dozen young patients.
“Right now, there is hope and excitement that we may have new therapies to introduce for these patients,” said Dr. Amar Gajjar of St. Jude, who is leading ongoing NCI-sponsored trials with the drug on behalf of the Pediatric Brain Tumor Consortium.
Meanwhile, the studies published to date suggest that patients in the Wnt subgroup tend to have very good outcomes, he noted. “So the clinical way forward for these patients is to see if we can judiciously cut back on chemotherapy and still maintain good outcomes.”
Since medulloblastoma was first described, in 1925, a tremendous amount has been learned about the biology of these tumors. Doctors can cure three out of four patients with this cancer, which was once uniformly fatal. The main challenge now, several researchers said, will be to improve on the existing survival rates while minimizing the side effects from treatment.
And, as Dr. Taylor and his colleagues noted in the conclusion of their report, researchers can now explore the idea of whether the molecular variants found in each subtype of medulloblastoma may in fact “constitute four distinct diseases.”
—Edward R. Winstead
full-text:
NCI Cancer Bulletin for January 25, 2011 - National Cancer Institute
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