02 2013
Journal of Cell Biology published our review on therapeutic advances in basal cell carcinoma treatment
Dependence of basal cell carcinomas and medulloblastomas on the Hedgehog pathway provides an opportunity for targeted or personalized therapy.
The recent effectiveness and FDA approval of the first Smoothened inhibitors
validates this class of agents, but has revealed drug-resistant tumor variants that bypass Smoothened inhibition.
One of the emerging themes in cancer biology is the dependence of cancer subtypes on certain signaling pathways for continued tumor growth. For example, mutations that activate the Hedgehog (Hh) signaling pathway drive growth of a variety of cancers including basal cell carcinomas (BCCs) and medulloblastomas, along with pancreatic, prostate, and small cell lung cancer that account for up to 25% of all human cancer deaths. BCCs are the most prevalent cancer in the world, and nearly half of all US citizens are likely to develop this cancer before retirement. Twenty years of extensive research identifying Hh pathway components and their functional roles recently culminated in the newly FDA approved Hh pathway antagonist vismodegib (Erivedge; Genentech/Roche) for the treatment of locally advanced or metastatic BCCs. Although vismodegib and other Smo inhibitors appear effective, treatment-driven tumor evolution has resulted in the outgrowth of tumor cell variants resistant to the drug. This rapid tumor evolution during treatment highlights the continued need to understand how tumors circumvent pathway blockade and identify new therapeutic targets for treating Hh-dependent cancers. In this article, we summarize the successful development of Hh pathway inhibitors and highlight promising areas for the development of next generation drug antagonists for Hh-dependent cancers.
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