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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. Here, we summarize the effectiveness of Hedgehog pathway inhibitors and highlight promising areas for the development of next generation drug antagonists for Hedgehog-dependent cancers.

[Figure][1] In Drosophila midguts treated with DSS, the number of proliferating cells (red) is reduced (right) when Hh signaling is inhibited in enteroblasts (green). [Tian et al.][2] reveal how Hedgehog (Hh) signaling prompts intestinal stem cells to proliferate in response to injury.

[Figure][1] HHIP1 (red) normally amasses in the neural tube’s basement membrane (arrowheads, left), but a version of the protein that can’t bind to heparan sulfate doesn’t accumulate there (right). Cells secrete an inhibitor that controls the distribution and activity of Hedgehog

Study reveals that dietary cholesterol regulates Hedgehog signaling and stem cell proliferation in flies.

[Figure][1] More follicle cells (red) surround the germ cells (blue) in ovaries lacking the Hh receptor Boi (right). The Hedgehog receptor Boi limits stem cell proliferation by retaining Hedgehog (Hh) at its source, [Hartman et al.][2] report. In Drosophila ovaries, Hh stimulates

Tukachinsky et al. reveal how Hedgehog (Hh) signaling in the primary cilium activates the Gli family of transcription factors. ![Figure][1] Gli transcription factors (top) and their inhibitor SuFu (bottom) are recruited to cilia upon Hh stimulation (right). In vertebrates, the Hh pathway