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Trimming the Hedgehog

A novel inhibitor of the hedgehog signaling pathway had promising results in patients with metastatic and aggressive local BCCs.

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.

Comment: This critical study has been a long time coming. Since the recognition of the hedgehog pathway's role in BCC, researchers have sought a therapeutic strategy targeting this pathway. The outcome in these patients was quite promising. Although metastatic BCCs are extremely rare, locally advanced BCCs are more common, and a future topical formulation of GDC-0449 could potentially increase the range of topical therapies for BCCs. Even more exciting is the prospect that a new treatment might be around the corner for other cancers influenced by the hedgehog signaling pathway.

— Hensin Tsao, MD, PhD

Published in Journal Watch Dermatology September 2, 2009

Citation(s):

Von Hoff DD et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 2009 Sep 2; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa05360)

Dlugosz AA and Talpaz M. Following the hedgehog to new cancer therapies. N Engl J Med 2009 Sep 2; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMe0906092)

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