Trimming the Hedgehog

Although basal cell carcinomas (BCCs) are a common, readily curable malignancy, treatment of metastatic BCCs and locally aggressive variants remains challenging. The presence of PTCH1 mutations in patients with Gorlin syndrome and SMO mutations in sporadic BCCs led to recognition of the role of the hedgehog signaling pathway in BCC development. PTCH1 inhibits expression and activity of the Smoothened membrane protein (encoded by SMO), which in turn sends signals inducing cell proliferation. Most BCCs have evidence of mutations that cause PTCH1 loss of function or that promote SMO signaling. Investigators supported or employed by the drug's discoverer recently tested the idea that inhibition of SMO signaling with a novel agent (the small-molecule inhibitor GDC-0449) might lead to a treatment for metastatic BCCs.

In a phase I trial, 33 patients with metastatic (18) or locally advanced (15) BCCs were given oral GDC-0449 at various doses ranging from 150 mg to 540 mg per day. Tumor responses to the therapy were assessed by the RECIST criteria. The median duration of treatment was 9.8 months. Of the 33 patients, 2 had complete response, 16 had partial response, 11 had stable disease, and 4 had progressive disease. There were no dose-limiting toxic effects.