A clinical study has demonstrated that a new drug, a targeted molecular therapy called vismodegib (trade name Erivedge™), can dramatically shrink basal cell skin cancers and prevent the formation of new ones, in patients with basal cell nevus syndrome (BCNS). This rare genetic condition causes dozens, and sometimes hundreds or thousands, of skin cancers on each patient's body. The primary treatment option is surgical removal. These study results are significant as they indicate the possibility of an alternative treatment with oral medication; although side effects remain a consideration.

The phase II clinical study, led by researchers at NewYork-Presbyterian Hospital/Columbia University Medical Center (NYPH/CUMC) and Children's Hospital of Oakland Research Institute (CHORI), was published June 6 in the online edition of the New England Journal of Medicine.

"In its current formulation, vismodegib is appropriate only for BCNS patients with very large numbers of basal cell skin cancers. Still, 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," said study co-leader David R. Bickers, MD, the Carl Truman Nelson Professor and chairman of dermatology at CUMC and director of dermatology at NewYork-Presbyterian Hospital/CUMC. The study was co-led by Ervin H. Epstein, Jr., MD, a senior scientist at CHORI.

The study is the first to evaluate vismodegib in patients with BCNS. Forty-two patients were randomized to receive either vismodegib (taken orally) or a placebo, for a maximum of 18 months. Overall, the study tracked more than 2,000 existing surgically eligible basal cell skin cancers (SEBs) and documented 694 new SEBs, on the 42 patients.

Patients taking vismodegib experienced an average of 2.3 new SEBs, compared with 29 for patients in the placebo group. Among patients taking the drug, the diameter of clinically significant skin cancers decreased an average of 65 percent, compared with 11 percent among controls. In light of these findings, the independent data and safety monitoring board appointed to oversee this trial recommended switching all patients into the treatment group.

"In many patients, we observed a dramatic reduction in the size of the lesions within one to two months," said Dr. Bickers.

BCNS, also called Gorlin syndrome, encompasses multiple defects that involve the skin, nervous system, eyes, endocrine glands, and bones. The hallmark of BCNS is the appearance of basal cell carcinomas, a slow-growing form of skin cancer, at or around puberty.

BCNS has been linked to mutations in a gene called PTCH1. PTCH1 is the primary inhibitor of a signaling pathway called sonic hedgehog, which helps ensure proper segmentation of the developing embryo. At birth, PTCH1 activity causes most sonic hedgehog signaling to cease. When PTCH1 is mutated, however, sonic hedgehog signaling continues postnatally. The result can be abnormal cell growth and proliferation, setting the stage for tumor formation.

Vismodegib was designed specifically to achieve targeted inhibition of the sonic hedgehog pathway, which is implicated in many types of cancer. The drug is manufactured by Genentech, Inc., of South San Francisco, CA.

Earlier clinical trials found vismodegib to be an effective treatment for metastatic and recurrent locally advanced basal cell skin cancer. On January 30, 2012, the Food and Drug Administration approved vismodegib for use in adults with these conditions who cannot be treated with surgery or radiation.

"Vismodegib is a new treatment option for those with extensive disease, particularly those whose lives may be devastated by the disease and the need for repeated treatment," Dr. Bickers said. However he would not recommend vismodegib for all BCNS patients. The side effects, which include loss of taste and appetite, weight loss, muscle cramps and hair loss, occur in nearly half of patients. Though not life threatening, they can be debilitating. Since patients would have to take vismodegib indefinitely, it is not a suitable alternative to surgery for patients with sporadic basal cell cancers.

"The purpose of the study was to see whether, by using this targeted molecular therapy, we could match the performance of a surgeon, and in many ways, we could," Dr. Bickers added. "The challenge now is to see if we can lessen the adverse effects while achieving the same therapeutic benefits -- by modifying the dosing schedule or perhaps by alternating drug treatment with other modalities such as photodynamic therapy, which can be effective for smaller lesions."

This is one of the first human cancer therapies based on determining the genetic mutations in a particular tumor pathway (in this case, sonic hedgehog) and inhibiting the pathway directly. The findings may have broader relevance to treating other types of basal cell skin cancer (the most common form of cancer in adults), which are caused by similar dysregulation of the sonic hedgehog pathway.

The paper is titled "Inhibiting the Hedgehog Pathway in Basal-Cell Nevus Syndrome Patients." Dr. Bickers' and Dr. Epstein's coauthors are Jean Y. Tang, MD, PhD; Julian M. Mackay-Wiggan, MD; Michelle Asterbaum, MD; Robert L. Yauch, PhD; Joselyn Lindgren, MS; Kris Change, BA; Carol Coppola, RN; Anita M. Chanana; and Jackleen Marji, MD.

The research was supported by the National Institutes of Health Clinical and Translational Science Awards (grant #UL1RR02413), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants #5P30AR044535-11 and #1K23AR056736), the Damon Runyon Cancer Research Foundation, and the Swim Across America Foundation.

This study was supported in part by Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY).