Targeting the hedgehog pathway: From bench to clinic

PL04-02

The Hedgehog (Hh) pathway is an ancient signaling cascade that directs patterning in most animals and is crucial for proper development. While Hh signaling is very active during most stages in embryogenesis, it remains relatively quiet in adult life. However, aberrant reactivation of the pathway in adult tissue can lead to the development of cancer. Hh pathway activation in tumors such as basal cell carcinoma (BCC) and medulloblastoma is the result of inactivating mutations in PATCHED (PTCH) or activating SMOOTHENED (SMO) mutations. Furthermore, in other solid tumors, such as colon and pancreas, Hh ligand expression is upregulated in tumor cells and acts in a paracrine manner to activate the pathway in the surrounding tumor stroma. A consequence of Hh pathway activation is the transcriptional upregulation of unique target genes and the expression levels of these transcripts that could serve as potential pharmacodynamic and predictive biomarkers of pathway activity. Targeting the Hh pathway with small molecule antagonists therefore provides new therapeutic opportunities for the treatment of both tumor types. GDC-0449, a systemic Hedgehog (Hh) pathway antagonist, was tested in a first-in-human, first-in class, Phase I study with locally advanced, multifocal or metastatic BCC patients. Antitumor activity was observed in BCC patients enrolled, thereby confirming the importance of inhibiting aberrant Hh signaling in tumors with mutations in the Hh pathway.