Abstract PL07-03: Targeting the hedgehog pathway in cancer

Abstract

Abstract 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 (1). 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. Targeting the Hh pathway with small molecule antagonists therefore provides a new therapeutic opportunity for the treatment of these tumor types. GDC-0449, a systemic Hedgehog (Hh) pathway inhibitor, was tested in a first-in-human, first-in-class, phase I study BCC patients. Strong anti-tumor activity was observed in patients with locally advanced, multifocal or metastatic thereby confirming the importance of inhibiting aberrant Hh signaling in BCC (2). In addition to its role in BCC and medulloblastoma, Hh pathway activation in other solid tumor types, such as pancreatic, ovarian or colon cancer is the result of upregulation of Hh ligand expression in epithelial tumor cells, which acts in a paracrine manner to activate the pathway in stromal fibroblasts (3, 4). These may in turn provide growth factor(s) and/or a microenvironement that promotes tumor growth directly or by affecting other compartments such as the vasculature. Inhibition of the Hh pathway may therefore also provide benefit in these tumors and is currently being explored in the clinic with GDC-0449. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PL07-03.