Stemming cancer by Hedgehog pathway inhibition: from flies to bedside
The past years of intense research on the role of major developmental signalling pathways and their implication in human diseases, have identified the Hedgehog, Wnt and Notch pathways as aetiologic factors in a wide variety of human malignancies. The Hedgehog signalling cascade, originally identified in the fruit fly Drosophila melanogaster, orchestrates a considerable number of developmental processes during vertebrate embryogenesis, including cell proliferation, survival, pattern formation, differentiation and stem cell fate. In the adult organism, however, the pathway is mostly inactive or only transiently activated during regeneration and healing, where Hedgehog signalling apparently controls stem cell activation and self-renewal. By contrast, many human malignancies such as cancers of the brain, skin, gastrointestinal tract or prostate display elevated and persistent activation of the Hedgehog pathway either in the bulk of tumour cells, the adjacent stromal compartment or in tumour-initiating cancer stem cells. Recent results from studies using different preclinical cancer models unambiguously show that uncontrolled Hedgehog pathway activation can induce or contribute to cancer development and growth and that targeted pathway inhibition is likely to offer an efficient therapeutic opportunity. We review here the oncogenic role of Hedgehog signalling, particularly the different mechanisms by which aberrant Hedgehog signalling affects malignant growth. We then focus on recent data from clinical trials that provide proof-of-concept for a striking therapeutic benefit for patients treated with small molecule Hedgehog pathway inhibitors.