October 26, 2004
New NIH grants support ambitious attacks on pediatric brain tumors
Thomas Roberts, PhD, and Charles Stiles, PhD
Scientists at Dana-Farber and Children's Hospital Boston have received two federal grants totaling more than $10.5 million to support their cutting-edge searches for the genetic causes of pediatric brain tumors, one of the most challenging forms of cancer.
One of the projects receiving this National Institutes of Health (NIH) funding is a hunt for cancer-causing mutations involved in two types of brain tumors. Investigators believe that these genetic errors might be corrected by drugs already on the shelves of pharmaceutical companies, but used for other purposes.
In the other effort, researchers are taking a systematic look at the role of genetic regulatory mechanisms that control the development of the brain in embryonic life and beyond. They chose this approach because the same genes that form the normal human brain can also go awry and cause brain tumors.
According to Charles Stiles, PhD, who heads the neuro-oncology program within Cancer Biology, the flagship goal of the latter project is to create an "atlas" of genes that manufacture regulatory proteins, known as transcription factors, which turn key genes on and off in the process of the brain's development.
Researchers at Children's Hospital Boston will be key collaborators on the project; they have access to samples of pediatric brain tumors from Children's and from other pediatric cancer centers across the country.
Such teamwork is familiar to Scott Pomeroy, MD, PhD, director of neuro-oncology at Children's, who has been a colleague of Stiles and others at DFCI since 1991. "We go way back, and have published many papers and taken care of many patients together. It's an invaluable collaboration."
Drugs may already exist
The first grant, from the National Cancer Institute, provides more than $3.5 million over five years to seek mutated genes that encode protein kinases in samples of pediatric brain tumors. Scientists will use the advanced technology of the Kinome Project, a DFCI-led search for mutant kinases, which behave like stuck "on" switches for cell growth and allow cells to proliferate out of control. Many such mutant kinases have been found in adult cancers, but haven't yet been sought in children's brain cancers.
"If we can find a mutant kinase, there's a fair chance the appropriate inhibitor already exists because the drug companies are so good at making them," says Thomas Roberts, PhD, of Cancer Biology, principal investigator on the project, along with William Sellers, MD. "The odds are we can get potential therapies relatively quickly." One example of an existing kinase inhibitor that works very well is the drug Gleevec, successful in treating chronic myelogenous leukemia (CML).
The kinase search will focus on medulloblastoma and low-grade astrocytomas, which together make up more than half of childhood brain tumors, notes Pomeroy.
The NIH's National Institute of Neurological Disorders and Stroke is funding the longer-range project for finding and characterizing transcription factors at a level of $7.17 million over five years. In addition to Stiles as principal investigator, co-investigators include Quifu Ma, PhD, of Cancer Biology and David Rowitch, MD, PhD, of Pediatric Oncology, as well as Children's Hospital's Pomeroy, Michael Greenberg, PhD, and Isaac Kohane, MD, PhD.
Stiles says that when the transcription factor atlas is completed, "we will make it available to the scientific community. There will be an ocean of work ahead, and we can't study all these transcription factors by ourselves."
