Cyclops Lambs Played Important Role in Vismodegib's Approval

MIAMI BEACH – A new therapy to combat advanced basal cell carcinoma is generating excitement in the few months since its Food and Drug Administration approval.

"Vismodegib provides substantial clinical benefit for patients with advanced basal cell carcinoma [BCC]," Dr. Scott M. Dinehart said at the South Beach Symposium. "For dermatology, this is a very important pathway." Through its novel ability to block a signaling pathway implicated in the development BCC, it can help treat "the kinds of terrible skin cancers where maybe you can operate on them or maybe not," said Dr. Dinehart, a dermatologist in private practice in Little Rock, Ark.

The FDA approved the oral, once-daily medication in January 2012 to treat adults with metastatic BCC or locally advanced, recurrent BCC after surgery. It is also indicated for patients with locally advanced BCC who are not candidates for surgery or radiation treatment.

Most side effects are mild to moderate, Dr. Dinehart said. "Muscle spasms are the one I am most worried about," he added, saying that such events might cause patients to discontinue use of the agent. Patients might also experience hair loss and taste changes because the hedgehog pathway is active in differentiation and proliferation of hair follicles and taste buds. "The side effects are the kind we can work around," Dr. Dinehart said.

Weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, and vomiting were other adverse events reported by 10% or more of participants in preclinical trials, according to the medication guide. Because of its teratogenicity, vismodegib carries a black box warning about embryo-fetal death and severe birth defects.

The hedgehog pathway inhibitor, vismodegib (Erivedge, Genentech), not only offers promise for patients with advanced BCC, but its approval also culminates a fascinating story of scientific discovery.

Five and half decades ago, in 1957, a herd of sheep in Idaho gave birth to one-eyed lambs. U.S. Department of Agriculture investigators determined that the "cyclops" lambs were born after dry weather drove the sheep to higher ground, where they ate corn lilies that contained a teratogenic toxin. They dubbed the toxin "cyclopamine."

The toxin blocks the segmentation of the brain and the two halves of the brain don’t separate during embryonic development, Dr. Brian Berman said in a separate presentation at the meeting. "Humans are also susceptible," added Dr. Berman, a professor of dermatology and cutaneous surgery at the University of Miami.

The toxin discovery probably would have remained a footnote in history, Dr. Dinehart said, except for scientists who looked at oncologic properties of this teratogenic compound. For example, Philip A. Beachy, Ph.D., while at Johns Hopkins in the early 1990s, cloned a hedgehog pathway gene in fruit flies that regulates embryonic cell differentiation. He observed that fruit fly embryos born with a faulty copy of the gene had a spiky or pointy appearance.

Dr. Berman said the most important of the hedgehog pathways in humans is called sonic hedgehog, which was named "after the Nintendo character with the spiky hair."

Dr. Dinehart said he is a consultant for Genentech. Dr. Berman is a consultant and a member of the speakers bureau for Genentech.

MIAMI BEACH – A new therapy to combat advanced basal cell carcinoma is generating excitement in the few months since its Food and Drug Administration approval.

"Vismodegib provides substantial clinical benefit for patients with advanced basal cell carcinoma [BCC]," Dr. Scott M. Dinehart said at the South Beach Symposium. "For dermatology, this is a very important pathway." Through its novel ability to block a signaling pathway implicated in the development BCC, it can help treat "the kinds of terrible skin cancers where maybe you can operate on them or maybe not," said Dr. Dinehart, a dermatologist in private practice in Little Rock, Ark.

The FDA approved the oral, once-daily medication in January 2012 to treat adults with metastatic BCC or locally advanced, recurrent BCC after surgery. It is also indicated for patients with locally advanced BCC who are not candidates for surgery or radiation treatment.

Most side effects are mild to moderate, Dr. Dinehart said. "Muscle spasms are the one I am most worried about," he added, saying that such events might cause patients to discontinue use of the agent. Patients might also experience hair loss and taste changes because the hedgehog pathway is active in differentiation and proliferation of hair follicles and taste buds. "The side effects are the kind we can work around," Dr. Dinehart said.

Weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, and vomiting were other adverse events reported by 10% or more of participants in preclinical trials, according to the medication guide. Because of its teratogenicity, vismodegib carries a black box warning about embryo-fetal death and severe birth defects.

The hedgehog pathway inhibitor, vismodegib (Erivedge, Genentech), not only offers promise for patients with advanced BCC, but its approval also culminates a fascinating story of scientific discovery.

Five and half decades ago, in 1957, a herd of sheep in Idaho gave birth to one-eyed lambs. U.S. Department of Agriculture investigators determined that the "cyclops" lambs were born after dry weather drove the sheep to higher ground, where they ate corn lilies that contained a teratogenic toxin. They dubbed the toxin "cyclopamine."

The toxin blocks the segmentation of the brain and the two halves of the brain don’t separate during embryonic development, Dr. Brian Berman said in a separate presentation at the meeting. "Humans are also susceptible," added Dr. Berman, a professor of dermatology and cutaneous surgery at the University of Miami.

The toxin discovery probably would have remained a footnote in history, Dr. Dinehart said, except for scientists who looked at oncologic properties of this teratogenic compound. For example, Philip A. Beachy, Ph.D., while at Johns Hopkins in the early 1990s, cloned a hedgehog pathway gene in fruit flies that regulates embryonic cell differentiation. He observed that fruit fly embryos born with a faulty copy of the gene had a spiky or pointy appearance.

Dr. Berman said the most important of the hedgehog pathways in humans is called sonic hedgehog, which was named "after the Nintendo character with the spiky hair."

Dr. Dinehart said he is a consultant for Genentech. Dr. Berman is a consultant and a member of the speakers bureau for Genentech.

MIAMI BEACH – A new therapy to combat advanced basal cell carcinoma is generating excitement in the few months since its Food and Drug Administration approval.

"Vismodegib provides substantial clinical benefit for patients with advanced basal cell carcinoma [BCC]," Dr. Scott M. Dinehart said at the South Beach Symposium. "For dermatology, this is a very important pathway." Through its novel ability to block a signaling pathway implicated in the development BCC, it can help treat "the kinds of terrible skin cancers where maybe you can operate on them or maybe not," said Dr. Dinehart, a dermatologist in private practice in Little Rock, Ark.

The FDA approved the oral, once-daily medication in January 2012 to treat adults with metastatic BCC or locally advanced, recurrent BCC after surgery. It is also indicated for patients with locally advanced BCC who are not candidates for surgery or radiation treatment.

Most side effects are mild to moderate, Dr. Dinehart said. "Muscle spasms are the one I am most worried about," he added, saying that such events might cause patients to discontinue use of the agent. Patients might also experience hair loss and taste changes because the hedgehog pathway is active in differentiation and proliferation of hair follicles and taste buds. "The side effects are the kind we can work around," Dr. Dinehart said.

Weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, and vomiting were other adverse events reported by 10% or more of participants in preclinical trials, according to the medication guide. Because of its teratogenicity, vismodegib carries a black box warning about embryo-fetal death and severe birth defects.

The hedgehog pathway inhibitor, vismodegib (Erivedge, Genentech), not only offers promise for patients with advanced BCC, but its approval also culminates a fascinating story of scientific discovery.

Five and half decades ago, in 1957, a herd of sheep in Idaho gave birth to one-eyed lambs. U.S. Department of Agriculture investigators determined that the "cyclops" lambs were born after dry weather drove the sheep to higher ground, where they ate corn lilies that contained a teratogenic toxin. They dubbed the toxin "cyclopamine."

The toxin blocks the segmentation of the brain and the two halves of the brain don’t separate during embryonic development, Dr. Brian Berman said in a separate presentation at the meeting. "Humans are also susceptible," added Dr. Berman, a professor of dermatology and cutaneous surgery at the University of Miami.

The toxin discovery probably would have remained a footnote in history, Dr. Dinehart said, except for scientists who looked at oncologic properties of this teratogenic compound. For example, Philip A. Beachy, Ph.D., while at Johns Hopkins in the early 1990s, cloned a hedgehog pathway gene in fruit flies that regulates embryonic cell differentiation. He observed that fruit fly embryos born with a faulty copy of the gene had a spiky or pointy appearance.

Dr. Berman said the most important of the hedgehog pathways in humans is called sonic hedgehog, which was named "after the Nintendo character with the spiky hair."

Dr. Dinehart said he is a consultant for Genentech. Dr. Berman is a consultant and a member of the speakers bureau for Genentech.