Results of an academic-industry partnership study demonstrate that targeting a single protein in the hedgehog pathway can block growth of cancer cells
The eradication of brain tumors in mice following treatment with a novel drug suggests that certain cancers might one day be cured without the use of toxic chemotherapy and radiation.
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.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
Published on PsychCentral.com. All rights reserved.
If you can keep your wits about you while others are losing theirs and blaming you, the world will be yours.