The gene, called Notch2, whose pathway is known to be an important factor in regulating brain stem-cell growth and survival, has been studied in fruit flies for almost a century. The research team at the Johns Hopkins Pathology Department and Kimmel Cancer Center found that a protein made by the Notch2 gene promotes cancer cell growth by 27 percent in a childhood brain tumor, called medulloblastoma. Their studies, reported in the November 1 issue of Cancer Research, also revealed that children with high Notch2 gene activity fared worse in the course of their disease than those with less activity in Notch2.
The researchers report that a drug first developed for Alzheimer's disease called DFK-167, which blocks activation of all Notch proteins, reduces growth of cancerous cells in culture by 80 percent, although unwanted side effects and dosing problems may make it a poor choice for treating human brain cancer. But the investigators are testing more potent drugs of the same class and developing new ones that block only the Notch2 pathway.
No clinical trials with any drug have yet been planned, the researchers emphasize.
Scientists say that gene amplification - a process in which cells make too many copies of a gene -- is one of the most reliable indicators of a gene's importance to cancer development. The Johns Hopkins team found Notch2 amplified in six of 40 (15 percent) medulloblastomas and other similar brain tumors.
"Just like genetic mutations, amplifications are long-lasting DNA mistakes, as opposed to transient changes in the production of proteins and other gene products," says Charles Eberhart, M.D., Ph.D., assistant professor of pathology at Johns Hopkins. "Finding amplification of Notch2 is a smoking gun tying it to the development of these brain tumors," he added.
In their study, the Johns Hopkins scientists compared levels of a protein marker for Notch2 gene activity to the survival of 35 medulloblastoma patients. Of 11 patients with high levels, seven died. Of 24 patients with no detectable protein, only six died.
Standard surgery and radiation for medulloblastoma cures approximately 60 percent of children, but often results in many neurological and learning disabilities.
"We'd like to develop a drug that only affects the Notch2 pathway, since blocking other members of the Notch family may actually have the opposite effect and encourage cancer growth," says Xing Fan, M.D., Ph.D., first author of the study and postgraduate fellow at Johns Hopkins.
In 25 of 30 of the medulloblastomas they studied, Eberhart's team also found lower levels of Notch1 gene products compared to Notch2. Notch1 proteins normally provide a brake on growth of medulloblastoma cells and blocking their activation would cancel out some of the drug's effects. "The net effect of any drug will depend on how much of each Notch1 and Notch2 is present, and since we found more Notch2, we think the scale can be tipped toward stopping the cancer," speculates Eberhart.
Close to 2,000 children are diagnosed with brain cancer annually in the United States. One in five childhood brain cancers is a medulloblastoma. The cancer originates in the back of the brain in the cerebellum. Medulloblastoma tumors often are characterized as looking like a large mass of stem cells.
This research was funded by the Children's Brain Tumor Foundation, National Institute of Neurological Disorders and Stroke, and the National Cancer Institute.
In addition to Eberhart and Fan, research participants include Irina Mikolaenko, Ihab Elhassan, XingZhi Ni, Yunyue Wang, and Douglas Ball from Johns Hopkins; Daniel Brat from Emory University; and Aire Perry from the Washington University School of Medicine.
Note: For more information on clinical trials at the Johns Hopkins Kimmel Cancer Center, visit www.hopkinskimmelcancercenter.org
Fan, Xing, et al, "Notch1 and Notch2 Have Opposite Effects on Embryonal Brain Tumor Growth." Cancer Research 64, November 1, 2004.
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