The Story of PTCH1

How patched 1 blocks the hedgehog pathway to treat skin cancer.

A pill that can be as effective as surgery in treating basal cell carcinoma owes its origins to one-eyed lambs and fruit fly babies that resemble hedgehogs.

The story of treating skin cancers arising from mutations in the patched 1 (PTCH1) gene on chromosome 9 begins with an apparent epidemic of lambs born in the western U.S. with one large eye – like the mythical Cyclops monster – in the 1950s. A sudden sweep of a birth defect suggests an environmental cause rather than an inherited one, and investigators from the United States Department of Agriculture (USDA) zeroed in on a pretty flowering plant called Veratrum californicum, the corn lily. The underground stems that crisscross subalpine meadows, along with most of the rest of the plant, harbor a toxin so strong that Native Americans poisoned their arrowtips with it and other cultures used the powdered root as an insecticide. Minuscule amounts kill.

The poison, a steroid alkaloid, affects lamb fetuses, but not older sheep. Researchers dubbed it “cyclopamine.” Other natural alkaloids work well as drugs, so researchers began to test cyclopamine, but it proved too toxic. However, discovering what cyclopamine does led to development of a drug called vismodegib (trade name Erivedge), which the Food and Drug Administration (FDA) approved in 2012 to treat metastatic, relapsed, and treatment-refractory basal cell carcinoma (BCC). The drug label has bold warnings of “embryo-fetal death and severe birth defects” that harken back to the sheep Cyclops.

The second story that led to development of Erivedge dates to 1980, when Christiane Nusslein-Volhard and Eric Wieschaus discovered a curious mutation that causes fruit fly larvae to sport spikes (“denticles”) and curl up, until they resemble tiny hedgehogs. The lamb Cyclops and bristly fly larvae share an underlying defect in development: body parts mix up back and front. In the one-eyed lambs, cells in the backs of the eyeballs migrate forwards as the front cells die, resulting in one huge, abnormal eye. In the fly, the normally naked back halves of the abdominal segments sport bristles, like the front parts normally do, in what one researcher describes as “a continuous lawn of denticles projecting from the larval cuticle.”

The mutant lambs and flies arise from defects in a cell signaling pathway named, appropriately, Sonic Hedgehog (SHH). (Fly geneticists are famous for vivid mutation names – genes related to Sonic Hedgehog are “armadillo” and “gooseberry.”) The SHH pathway is very active in the embryo, helping body parts to sort themselves out correctly, then quiets down after birth. If the SHH gene remains fully “on” after birth, cancer results.

In 1991 researchers discovered that the patched 1 gene encodes the receptor for Sonic Hedgehog protein, and that the pathway is vitally important in embryonic development. The following year came evidence that PTCH 1 mutations cause the rare basal cell carcinoma nevus syndrome (BCCNS, aka Gorlin
syndrome). Biotech giant Genentech (now a Roche company) spent much of the 1990s panning for pharmaceutical gold: a compound that inhibits overactive hedgehog signaling, either via the PTCH1 protein, or through a protein with which PTCH1 associates, called smoothened (SMO).

The two stories converged in 2000, when researchers at Johns Hopkins University discovered that cyclopamine – the poison behind the single-eyed lambs – inhibits Hedgehog signaling. The Genentech researchers could immediately narrow their drug search.

PTCH1 and SMO proteins embed in fatty areas of the cell membrane colorfully called lipid rafts, where they contact each other and hold aloft the SHH protein. The relationship among the three proteins is like someone crowdsurfing at a concert, the floor analogous to the cell membrane and PTCH1
and SMO to the people holding up the surfer. By 2004, Genentech had a candidate drug, “GDC-0449,” which worked by pulling PTCH1 slightly away from its partner SMO, so that SHH is no longer held above the cell membrane, where it would otherwise initiate signals to divide.

The candidate drug performed well in non-human animals and in human cells in culture, but as a topical treatment on an intact person, it didn’t penetrate the skin sufficiently. Genentech decided to pursue an oral delivery, and filed GDC-0449 as an investigational new drug with FDA in 2006. A clinical trial of the drug in metastatic or locally advanced BCC, and on colorectal cancer and post-remission ovarian cancer began in 2008. In 2009 the company published a case report on drug use against medulloblastoma, a lethal brain cancer.

The drug became Erivedge. Other approvals beyond BCC may follow, because at least 19 cancers involve the Hedgehog signaling pathway. Next will likely be basal cell carcinoma nevus syndrome, which is the rare inherited form of the cancer. People with BCCNS inherit a susceptibility mutation in every cell, and cancer develops when and where a second mutation occurs. Researchers from Genentech and three clinical centers published results of their trial of Erivedge to treat BCCNS in June 2012. Of 41 patients who had more than 2,000 skin cancers among them, 26 received the drug and the rest placebo. Results were striking. Only two new cancers appeared among the treated patients over the 17 months of the trial, versus 29 among the placebo group, and the treated patients’ cancers shrunk by 65 percent compared to 11 percent with placebo. Of biopsies taken from treated patients whose cancers had regressed, 83 percent showed no signs of cancer.

Once the drug’s formulation is altered to dampen the side effects (cramps and loss of hair, weight, and sense of taste), it may vastly improve quality of life for patients with BCCNS, who typically have hundreds or thousands of skin cancers over their lifetimes, and many surgeries. Said one of the investigators, David R. Bickers, MD, director of dermatology at New York-Presbyterian Hospital/Columbia University Medical Center, “this is a huge step forward, pointing to the day when we can offer every one of these patients an alternative to repeated surgery, which can be disfiguring and
burdensome.”

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