From the Departments of Molecular Biology, Exploratory Clinical Development, and BioOncology, Genentech, Inc., South San Francisco, CA
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Frederic J. de Sauvage, PhD, Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA; e-mail: desauvage.fred{at}gene.com
Overview: The Hedgehog (Hh) pathway is an evolutionarily conserved cascade that directs patterning in most vertebrates and is crucial for proper development. Although it is active during most stages of embryogenesis, Hh signaling remains relatively quiescent in the adult. Reactivation of the pathway in adult tissues can lead to tumor development and has most frequently been observed in tumors such as basal cell carcinoma (BCC) and medulloblastoma. In most cases of BCC and in up to 30% of medulloblastomas, aberrant Hh signaling is driven by either inactivating mutations in PATCHED (PTCH) or activating SMOOTHENED (SMO) mutations. In other tumor types, such as pancreatic cancer, Hh pathway activation is the result of upregulation of Hh ligand expression by tumor cells. Hh ligand may drive tumor growth and survival by activating the pathway in the tumor stroma in a paracrine manner. Herein we provide an introduction to the important components of the Hh pathway and the mechanistic hypotheses that portray their functions, and we describe efforts to develop small molecule inhibitors of the Hh pathway to provide new therapeutic opportunities for the treatment of cancer.
