WEDNESDAY, Sept. 2 (HealthDay News) -- An experimental cancer drug that switches off the so-called "Hedgehog" pathway beat back tumors in more than half of patients with advanced basal cell carcinoma, a type of skin cancer.
The drug also helped a 26-year-old man suffering from medulloblastoma, the most common form of brain cancer in children.
"We were both pleased and surprised. We had hoped that we might see responses like this but we in no way anticipated that, within the context of a phase 1 clinical trial, we would see this level of anti-tumor activity," said Dr. Charles M. Rudin, who authored two papers on the findings that appear in the Sept. 2 online edition of the New England Journal of Medicine. "These are the first reports in the literature of any Hedgehog inhibitor being used clinically."
Phase 1 trials are conducted to look at a drug's safety profile and determine the right dose. Phase 2 and phase 3 trials typically look at effectiveness.
Also exciting, however, is the fact that the Hedgehog pathway has been implicated in other cancers, notably colon cancer and ovarian cancer, albeit in a different way.
Researchers are going forward to look at the potential of the molecule, known as GDC-0449, to treat these types of cancers as a one-drug regimen, and in combination with other drugs for other solid tumor malignancies, said Rudin, who is associate director for clinical research at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.
One expert noted that finding a compound that might control the Hedgehog pathway could have far-reaching implications.
"These are phase 1 trials so they're quite preliminary, but the drug is quite effective in at least a subset of the patients treated," said Dr. Andrzej Dlugosz, author of an accompanying editorial and a professor in the department of dermatology at the University of Michigan Medical School and Comprehensive Cancer Center in Ann Arbor. "The reason we're so excited is that there are now a large number of cancers that have also been linked to abnormalities in this pathway, including pancreatic, colon, ovarian and prostate. It's quite an impressive list. The data is pretty strong suggesting that if you shut down the pathway, it can have a pretty profound effect on those tumor cells. If it can work in these cancers, maybe it can work in other cancers, even though the signaling there is more complex."
But another researcher warned that it is premature to get too excited about the results.
"It's great to see something with so much potential, but it really is potential," said Dr. Clifford Perlis, director of Mohs Micrographic Surgery and Dermatologic Surgery at Fox Chase Cancer Center in Philadelphia.
However, he added, "there are other companies developing Hedgehog inhibitors as well, so I think people should be paying attention to this."
The Hedgehog gene, so named because it was first discovered in flies with hair resembling the spikes of hedgehogs, "is really important during early embryonic development in pretty much all animal species from flies to mice to humans, and for pretty much every tissue you can imagine," explained Frederic de Sauvage, also an author on both papers. "But remarkably in adults, it seems to be mostly turned off."
De Sauvage is vice president of research, molecular biology, at Genentech, which developed the molecule and funded the study.
Some 1 million Americans get basal cell carcinoma each year. It often doesn't spread but, once it has, there are no approved treatments. Medulloblastoma is an aggressive form of brain tumor.
The first trial enrolled 33 individuals whose basal cell carcinoma had spread locally or to distant organs.
Half of the participants who had distant metastases saw a reduction in tumor size, as did 60 percent of those with locally advanced cancer. The rest had either stable or progressive disease after 10 months of follow-up.
But "stable" in this population may not mean much, Perlis pointed out, as it is generally a very slow-growing cancer.
The man with medulloblastoma also saw a significant shrinkage of his tumor, along with vastly improved quality of life, but only for two months. He later died.
A third study by some of the same authors, this one published online Sept. 2 in Science Express, discovered that treatment with GDC-0449 actually spurred another mutation in a gene called SMO, which caused the brain tumor to become resistant to the drug.
Because the Hedgehog pathway does not actually do much in adults, side effects were minimal, said de Sauvage.
GDC-0449 would likely be used very differently, depending on which type of cancer it is targeting.
In the case of basal cell carcinoma and medulloblastoma, the mutation in the Hedgehog pathway "really drives the formation of these tumors," de Sauvage said. "This molecule inhibits the pathway very specifically and, to date, we only know of these two types of tumor where the pathway is mutated." That means GDC-0449 is effective on its own.
But in colon and ovarian cancer, he continued, the pathway recruits surrounding cells to promote the cancer. In these types of tumors, GDC-0449 would have to be combined with other drugs.
The American Academy of Dermatology has more on basal cell carcinoma.
SOURCES: Clifford Perlis, M.D., director, Mohs Micrographic Surgery and Dermatologic Surgery, Fox Chase Cancer Center, Philadelphia; Andrzej Dlugosz, professor, department of dermatology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor; Frederic de Sauvage, Ph.D., vice president, research, molecular biology, Genentech; Charles M. Rudin, M.D., Ph.D., associate director, clinical research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore; Sept. 2, 2009, New England Journal of Medicine, online; Sept. 2, 2009, Science Express, online