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Scientists at St. Jude have generated new models of medulloblastoma tumors by inactivating different DNA repair pathways, specifically in the brain. Investigators found that in all medulloblastomas a gene called Patched 1 (Ptch1) was inactivated, showing that this gene plays an important role in medulloblastoma. The approach offers promise for understanding other types of brain tumors and developing new treatments for these cancers.
“Although medulloblastoma is a particularly devastating brain tumor in children, there have been great advances in successful treatment strategies,” said Peter McKinnon, PhD, Genetics and Tumor Cell Biology. “Nevertheless, the cure rate is still only about 70 percent, so any new molecular insights are important to enable us to continue to increase the effectiveness of treatments.”
The researchers published their findings online in the January 21 edition of Proceedings of the National Academy of Sciences. McKinnon is the paper’s senior author.
Medulloblastoma and many other cancers can originate with the failure of the cell’s machinery for repairing broken DNA segments. This failure can cause broken DNA— prompting affected chromosomes to stitch themselves together in abnormal arrangements that can switch genes on or off. Some of these aberrant gene activations or inactivations trigger cancers.
In their experiments, McKinnon and his colleagues set out to discover the consequences of switching off DNA repair in the proliferating brain cells of young mice. The researchers used a conditional knockout technique that allowed them to selectively block the action of only certain types of DNA repair processes and only in the brain.
The investigators found that the engineered mice invariably developed medulloblastoma. The researchers analyzed the tumor cells in the animals to discover whether the tumors had a malfunctioning gene in common.
“We had damaged the DNA repair system that allowed mutations to accumulate in an unbiased way—mimicking what might happen in a proliferating brain cell—and we could then ask what genes were important in causing medulloblastoma as a result of this damage,” McKinnon said. “We found that in every case, a gene that malfunctioned was Patched 1.”
The finding of Ptch1’s importance in medulloblastoma makes sense because the functioning gene normally acts as a brake on cell growth, thereby suppressing tumors, McKinnon said. Importantly, the loss of the Ptch1 brake also occurs in the human brain and in other tumors.
Not only did these mice lose the brake of Ptch1, but their mixed-up chromosomes also caused amplification of a small group of other genes that accelerated cell growth. This supercharged growth helps propel the cells that lack Ptch1 on their road to malignancy.
“We believe that these findings are important, not only because they demonstrate the significance of Patched 1 in medulloblastoma, but because the approach shows only a small number of genetic changes are responsible for the development of the cancer,” McKinnon said.
The ability to create such mouse models of tumors by precisely engineering a genetic defect in only certain brain cells offers valuable experimental models for understanding medulloblastomas, as well as other brain cancers, McKinnon said.
“This work has told us how useful this tissue-specific inactivation approach can be for understanding tumors like medulloblastomas arising from certain cells,” he said. “We can now channel the inactivation of these repair genes to other specific subsets of brain cells to generate animal models of other brain tumors.”
McKinnon also noted that the animal models provide a useful test bed for determining the clinical value of existing chemotherapies, as well as a range of new therapies that target the DNA repair pathway.
Other authors of this paper include Youngsoo Lee, PhD, Helen Russell, PhD, and Jingfeng Zhao, all of Genetics and Tumor Cell Biology; Nader Chalhoub, PhD, and Suzanne Baker, PhD, both of Developmental Neurobiology; Yong-Dong (Michael) Wang, PhD, Hartwell Center for Bioinformatics and Biotechnology; and Pierre-Olivier Frappart and Kenji Orii, formerly of St. Jude.
This research was sponsored in part by the National Institutes of Health and ALSAC.