This finding, by investigators at St. Jude Children's Research Hospital, is published in the current issue of Cancer Cell. The type of tumor successfully treated--medulloblastoma--is the most common malignant brain cancer in children, accounting for about 20 percent of all pediatric brain tumors. Medulloblastoma arises in the cerebellum, the part of the brain that helps coordinate movement and contributes to learning motor skills.
The St. Jude team treated the mice with oral doses of HhAntag, a compound known to block the function of a molecule called smoothened (Smo). The suppression of Smo also suppressed several genes that are critical to triggering and driving the tumor's proliferation. This action inhibited cell proliferation and led to the death of tumor cells, resulting in the regression of medulloblastoma.
The Smo protein is part of a biochemical cascade of reactions called the Sonic Hedgehog pathway (Shh). The Shh pathway triggers normal growth of the cerebellum in the fetus, but its abnormal activity during infancy and early childhood causes medulloblastoma.
The mice in the study were specially bred to lack one of the two copies of a gene called patched-1 (Ptc1), and to lack both copies of the gene p53. The Ptc1 gene blocks abnormal growth of nerve cells, and p53 causes tumor cells to self-destruct. Normally the mice would have two of each gene, one inherited from each parent. The loss of one Ptc1 gene and both p53 genes caused all of the mice to develop medulloblastoma.
The eradication of medulloblastoma in mice by blocking a single protein is proof that the concept of treating certain cancers using a so-called "magic bullet" against a specific target in the cell is a realistic goal for treating some tumors, according to Thomas Curran, Ph.D., chair of the department of Developmental Neurobiology at St. Jude. The finding holds promise for developing new drugs to treat brain cancers--or subtypes of brain cancers--that do not require additional, potentially toxic therapies. This approach to targeting the Shh pathway might also work for other cancers, such as basal cell carcinoma (a skin cancer), as well as lung and gastrointestinal cancer.
Curran is senior author of the Cancer Cell report.
The study also fulfilled the promise of using mouse models of cancer to study specific diseases and test novel therapeutic compounds in pre-clinical investigations in preparation for studies.
"This work could not have been done without mouse models," Curran said. "The hedgehog pathway does not work when studied in tumor cells cultured in dishes. Only the intact animal studies were able to allow us to make the extremely important observations that HhAntag can halt and reverse an otherwise fatal cancer."
The St. Jude team demonstrated that the highest dose of HhAntag--100 mg/kg (i.e., 100 milligrams of drug per kilogram of body weight) twice daily for four days--completely suppressed the Shh pathway. In addition, the mouse brains showed a decrease in total tumor mass. Three-week old mice with tumors, treated twice daily for the longer time of two weeks at 20 mg/kg had much smaller tumors than untreated mice. In mice treated with 100 mg/kg twice a day for two weeks, no tumor mass could be detected, and the structure of the cerebellum was restored to normal.
When mice were treated for a prolonged period of time, with an intermediate dose of 100 mg/kg once daily, they stayed tumor-free significantly longer than untreated mice, and they showed no side effects of the drug. However, since this lower dose did not permanently eliminate the cancer, careful studies designed to determine the best dosing regimen are needed before the Shh inhibitors are taken to the clinic.
"These preliminary findings suggest that long-term treatment with HhAntag should be considered for trials in patients, with the hope that it will similarly prolong cancer-free survival in humans," sais Justyna T. Romer, Ph.D., of St. Jude Developmental Neurobiology. "Long-term treatment might even permanently eradicate the cancer in some patients. In fact, some of the mice in our study responded to the treatment so quickly that their tumors apparently did not have time to develop resistance to the drug. We're investigating that possibility in further studies now."
Romer is lead author of the Cancer Cell paper.
The St. Jude study reflects a goal of the National Cancer Institute for exploiting academic/industry partnerships to make breakthroughs in the treatment of cancer. The biotechnology company Curis (Cambridge, Mass.) developed HhAntag and collaborated on the research. "Our work with Dr. Curran demonstrates that this orally administered drug effectively blocks the hedgehog pathway in a mouse model that is truly representative of medulloblastoma," said Lee L. Rubin, Ph.D., Curis senior vice president of research and chief scientific officer. "We look forward to continuing our collaboration with St. Jude to make this drug available to treat medulloblastoma."
Curran said that further collaborations are forthcoming.
Other authors of the study are Hiromichi Kimura, Susan Magdaleno, Ken Sasai, Christine Fuller, Helen Baines, Michele Connelly, Clinton F. Stewart (St. Jude); and Stephen Gould (Curis).
This work was supported in part by a Cancer Center Support (CORE) grant from NIH and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tennessee, St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit www.stjude.org.