Dramatic response: Experimental agent inhibits aberrant Hedgehog signaling pathway

Key Points

San Diego - Advanced basal cell carcinoma responded dramatically to an experimental agent that inhibits the aberrant Hedgehog signaling pathway, according to a study presented at the American Association of Cancer Research annual meeting.

GDC0449 (Genentech BioOncology) produced impressive responses in a first-in-human, first-in-class phase 1 study of nine advanced, multifocal or metastatic basal cell carcinoma patients.

Durable clinical benefit (tumor shrinkage or disease stabilization) was observed in eight of nine patients, for a median of 176 days, according to Daniel D. Von Hoff, M.D., physician-in-chief at the Translational Genomics Research Institute and chief medical officer for the Scottsdale Clinical Research Institute, Scottsdale, Ariz.

Abnormal activation of the Hedgehog pathway because of mutations at these sites is critical to the development of both hereditary and sporadic human basal cell carcinomas.

Dose-escalation study

In a dose-escalation study, patients received 150, 270 or 540 mg of GDC0449 given orally as a single daily dose on a continuous 28-day schedule.

"The first patient had widespread metastases to the lung, liver and bone. He had a dramatic response to the drug, and has shown clinical improvement for over 438 days, with only mild side effects," Dr. Von Hoff tells Dermatology Times.

Of the original nine patients, two have had tumor shrinkage as measured by CT scans, four have had improvement by clinical examination, two have had prolonged periods without tumor growth, and only one has experienced disease progression.

In several patients, investigators observed nearly complete disappearance of skin lesions, even in two patients with lung metastases, he says.

Further evaluations

Further evaluations measured the presence of GLI1, a genetic marker of Hedgehog pathway activity, in skin cells sampled from the participants.

In all patients tested to date, this marker has been reduced by at least twofold, indicating that the drug is, indeed, affecting the Hedgehog pathway, he says.

"The drug has been extremely well-tolerated," Dr. Von Hoff says. "Some patients lose a sense of taste, and we have observed a small amount of alopecia and weight loss, but the toxicity has generally been mild."

Dr. Von Hoff calls the research "the essence of translational medicine."

He says, "We did a tremendous amount of preclinical work showing that PTCH and SMO mutations are associated with basal cell carcinoma. They activate the Hedgehog pathway. We've found a specific compound that inhibits this pathway, and we've gotten a clinical response."

Ervin Epstein, M.D., of Children's Hospital and Research Center, Oakland, Calif., says that basal cell carcinoma is the most common human cancer, occurring in at least one in four Caucasians. In the sporadic form, which is especially common, the typical presentation is the development of several tumors after age 50.

With the heritable form, however, tumors are numerous, beginning in the teens. While basal cell carcinomas enlarge slowly, invade locally and rarely metastasize, when they do advance, they are very problematic.

Dr. Epstein, who has conducted research in dermatology for many years, suggested that GDC0449 may be working by treating stem cells, since "it takes a while for it to work," he says.

"If 'all' cancers have stem cells and if Hedgehog is required for cancer stem-cell maintenance, then Hedgehog inhibition might be active in other cancers," Dr. Epstein says.

It may also work by producing a cellular effect (apoptosis/necrosis, inhibition of proliferation or differentiation) or by inhibiting gene expression.

Adverse effects need to be studied, he says, as transient inhibition of the Hedgehog pathway has been shown to produce permanent defects in bone structure and to affect short-term memory in young mice.

In the meantime, he says, "For those patients with sheets of basal cell carcinomas on their skin, help may be on the way."