Genentech has filed a new drug application with the US Food and Drug Administration for vismodegib, a Hedgehog (HH) pathway inhibitor that has shown promising results in a Phase II trial in patients with advanced basal cell carcinoma (BCC).

The results of the trial, which enrolled 104 patients, were presented at the seventh European Association of Dermato-Oncology meeting earlier this year. Vismodegib was found to substantially shrink tumours or heal visible lesions in 43% of patients with locally advanced BCC and in 30% of patients with metastatic BCC.

Some cancers — such as BCC, the most common cancer in the western world, and medulloblastoma, a childhood cancer with a poor prognosis — are associated with mutational activation of HH signalling in the absence of the ligand, which directly drives tumour cell proliferation (Nature Rev. Drug Discov. 5, 1026–1033; 2006). In other cancers, such as pancreatic adenocarcinoma and small-cell lung cancer, overexpression of HH ligands by tumour cells drives cancer progression by increasing the production of growth and angiogenic factors from neighbouring cells.

“HH pathway inhibitors could provide new hope to patients with these cancers,” says James K. Chen, Department of Chemical and Systems Biology, Stanford University School of Medicine, California, USA. “As HH signalling is not generally required for cell growth and function, vismodegib and other drugs that target this pathway may also avoid the side effects associated with conventional chemotherapies,” he adds.

Vismodegib inhibits HH signalling by targeting the G protein-coupled receptor-like protein Smoothened (SMO). The only known function of SMO is to mediate HH signalling, so SMO-targeting drugs can be highly specific for this oncogenic pathway. “SMO is attractive because it was the first target in the HH pathway shown to be amenable to pharmacological intervention [Science 280, 1603–1607; 1998; Nature 406, 1005–1009; 2000; Genes Dev. 16, 2743–2748; 2002], and is a commonly encountered target in small-molecule screening [Proc. Natl Acad. Sci. USA 99, 14071–14076; 2002]. Several cyclopamine mimics (SMO-binding HH pathway antagonists), including a derivative of cyclopamine itself, are currently in clinical trials,” explains Philip Beachy, Institute for Stem Cell Biology and Regenerative Medicine, Stanford, California, USA.

However, the development of resistance to drugs that target SMO might be a problem, as “there are likely to be mutations in SMO or other types of acquired drug resistance that diminish the effectiveness of some SMO antagonists”, cautions Lee Rubin, Director of Translational Medicine at the Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. “It may be preferable to find a drug that inhibits a downstream component of the HH signalling pathway, such as [the transcriptional activator] GLI, but whether such compounds will be able to achieve the same degree of pathway specificity as SMO antagonists remains to be seen.”

In addition, SMO inhibitors might not be effective in all types of cancer that involve aberrant HH signalling. In some cancers HH may not be the sole driver of tumour growth. “In these cancers, HH antagonists may need to be combined with other inhibitors,” adds Rubin. “Nevertheless, these findings are very exciting and it will be interesting to see how effective vismodegib is against other tumours linked to HH pathway activation.”

After a long series of basic science investigations, beginning with the genetic characterization and isolation of the hh gene in Drosophila melanogaster in the 1980s and 1990s, these findings with vismodegib highlight the clinical potential of targeting HH signalling for the treatment of cancer in humans. The trials that are currently underway with vismodegib and other HH inhibitors should reveal which tumours these drugs might be useful for. “Finding ways to prevent or overcome resistance mechanisms will also be integral to the implementation of HH pathway-targeting chemotherapies,” concludes Chen.