Experimental Drug Shows Promise for Several Cancers

In the first clinical proof of its kind, a drug has dramatically shrunk cancerous tumors by disrupting a key genetic pathway. But a study targeting one deadly brain cancer, medulloblastoma, ended in disappointment as the patient's once-tamed tumor quickly developed resistance to the drug and killed him.

The drug, GDC-0449, was developed at Genentech in South San Francisco, California. It locks onto and deactivates a protein, Smoothened, that activates the Hedgehog signaling pathway, which orchestrates how embryonic stem cells develop. In adults, the Hedgehog pathway is dormant, but it awakens in many cancers.

Dramatic but transient. Within 2 months, a novel drug candidate shriveled a man's metastasized cancer (center). One month later, the cancer, now resistant, resurged.

In a paper published online today in The New England Journal of Medicine (NEJM), scientists treated 33 people with one such cancer, basal cell carcinoma, a common skin cancer. The carcinoma had advanced so far that conventional treatments were useless. Nevertheless, after a median treatment of 10 months, 18 patients improved substantially on the drug, and it arrested the spread of cancer in 11 others. Scientists have long suspected that disrupting the Smoothened-Hedgehog link would shrink tumors without messy radiation or chemotherapy. Now they have proof.

Still more dramatic was the response of a 26-year-old man with medulloblastoma, reported in a second paper in NEJM. Hedgehog signals have been implicated in one-third of human medulloblastoma cases. It's an aggressive cancer, and tumors had colonized the man's entire body. "He came in very sick, thinned, in a lot of pain, not very active, needing frequent blood transfusions," says Charles Rudin, associate director of clinical research at Johns Hopkins University in Baltimore, Maryland, who treated the patient. "His prognosis was terrible."

Other treatment options, including radiation, had failed, so in late April 2008, Rudin began giving the man 540 mg of GDC-0449 daily. By 23 June, he had gained 7 kilograms and reported that he was in far less pain than before. He even began exercising again. The numerous blotches on his positron emission tomography (PET) scans had been reduced to a few isolated islands of cancer (see picture). But on 23 July, a PET scan revealed that the cancer had returned in a resistant form and was almost as widespread as before. "It was a big disappointment," says Rudin. The young man died 23 September.

GDC-0449 seems promising for skin cancer, say several experts, and Genentech has already moved into phase II clinical trials. It remains unclear how well the drug will work for medulloblastoma, however. This brain cancer usually targets children (the median age of victims is 5), and because the Hedgehog pathway controls aspects of skeletal development, shutting it off might not be safe. The class of compounds that includes GDC-0449 could also help contain other cancers, such as ovarian and colorectal cancers, that are not triggered in the same way as medulloblastoma or basal cell carcinoma but that are still partly driven by aberrant Hedgehog signaling. Genentech is already testing drugs along these lines.

Meanwhile, in a separate study published online today in Science, an overlapping team at Genentech led by biologist Frederic de Sauvage describes the mechanism by which the man's brain tumor developed resistance. The team found that a point mutation in Smoothened, a G-to-C substitution at position 1697 along the protein's length, prevented GDC-0449 from binding but did not alter the ability of Smoothened to switch on the Hedgehog pathway.

Further research showed that a similar resistance had developed in mice with mutated medulloblastoma. The point substitution was different but occurred in the exact same spot and interfered with the drug in the same way. That correspondence between humans and mice hints that preventing drugs like GDC-0449 from locking onto Smoothened could be a common way to develop resistance. However, scientists can now study the resistance, and they hope to devise ways around it.

Tom Curran of Children's Hospital of Philadelphia in Pennsylvania praises the papers for providing a firm basis for understanding Smoothened-related cancers. "It's a landmark study and will raise a lot of questions about how to proceed with personalized medicine in the future," he says.

By Sam Kean
ScienceNOW Daily News
2 September 2009


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