Targeting the Hedgehog pathway in cancer

Abstract

The Hedgehog (Hh) pathway is a major regulator of many fundamental processes in vertebrate embryonic development including stem cell maintenance, cell differentiation, tissue polarity and cell proliferation. Constitutive activation of the Hh pathway leading to tumorigenesis is seen in basal cell carcinomas and medulloblastoma. A variety of other human cancers, including brain, gastrointestinal, lung, breast and prostate cancers, also demonstrate inappropriate activation of this pathway. Paracrine Hh signaling from the tumor to the surrounding stroma was recently shown to promote tumorigenesis. This pathway has also been shown to regulate proliferation of cancer stem cells and to increase tumor invasiveness. Targeted inhibition of Hh signaling may be effective in the treatment and prevention of many types of human cancers. The discovery and synthesis of specific Hh pathway inhibitors have significant clinical implications in novel cancer therapeutics. Several synthetic Hh antagonists are now available, several of which are undergoing clinical evaluation. The orally available compound, GDC-0449, is the farthest along in clinical development. Initial clinical trials in basal cell carcinoma and treatment of select patients with medulloblastoma have shown good efficacy and safety. We review the molecular basis of Hh signaling, the current understanding of pathway activation in different types of human cancers and we discuss the clinical development of Hh pathway inhibitors in human cancer therapy.

Keywords: GDC-0449; Hedgehog; basal cell carcinoma; cancer stem cells; medulloblastoma.

Figure 1.

Hedgehog signaling pathway in vertebrates. The above model illustrates our current understanding of the vertebrate Hedgehog (Hh) pathway signaling. Hh signaling cascade is initiated in the target cell by the Hh ligand binding to the Patched 1 protein (PTCH), a 12-span transmembrane protein located on the plasma membrane. Smoothened (SMO), a 7-transmembrane-span protein receptor, is located on the membrane of the intracellular endosome. In mammalians, the Hh signaling takes place in the nonmotile cilia to which the SMO and other downstream pathway components transit to in order to activate the GLI transcription factors [Rubin and de Sauvage, 2006; Corbit et al. 2005; Huangfu and Anderson, 2005; Huangfu et al. 2003]. An endogenous small molecule acting as a SMO agonist is transported outside the cell by PTCH, preventing its binding to SMO. In the absence of a Hh ligand, PTCH catalytically inhibits the activity of SMO by affecting its localization to the cell surface. Full-length GLI proteins are thus proteolytically processed to generate the repressor GLI^R, largely derived from GLI 3, which represses Hh target genes. Binding of Hh to PTCH, internalizes and destabilizes PTCH, so that it can no longer transport the endogenous SMO agonist molecules outwards. Intracellular accumulation of this agonist molecule activates SMO which translocates to the plasma membrane, apparently concentrating in the cilia. Relief of SMO inhibition promotes generation of the activator GLI^A, largely contributed by GLI 2 and the subsequent expression of the Hh target gene [Taipale et al. 2002]. CK1α, casein kinase 1α; GPCR, G-protein-coupled receptor; GSK3β, glycogen synthase kinase 3β; PKA, protein kinase A. Reprinted by permission from Macmillan Publishers Ltd: Rubin, L.L. and de Sauvage, F.J. (2006) Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5: 1026–1033.

Figure 2.

Different models of Hedgehog pathway signaling. (A) Type I ligand-independent cancers harbor inactivating mutations in Patched 1 protein (PTCH) or activating mutations in Smoothened (SMO) leading to constitutive activation of the Hedgehog (Hh) pathway even in the absence of the Hh ligand. (B) Type II ligand-dependent autocrine cancers both produce and respond to the Hh ligand leading to support tumor growth and survival. (C) Type III ligand-dependent paracrine cancers secrete the Hh ligand which is received by the stromal cells leading to pathway activation in the stroma. The stroma in turn feeds back various signals such as IGF, Wnt, VEGF to the tumor tissue leading to its growth or survival. (D) Type IIIb reverse paracrine tumors receive Hh secreted from the stroma leading to pathway activation in the tumor cells and upregulation of survival signals. (E) Cancer stem cells (CSCs): Hh signaling occurs only in the self-renewing CSCs, from the Hh ligand produced either by the CSCs or by the stroma. CSC will give rise to more Hh pathway dependent CSCs or possibly may differentiate into Hh-pathway negative tumor cells comprising the bulk of the tumor. Reprinted from: Scales, S.J. and de Sauvage, F.J. (2009) Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci 30: 303–312, with permission from Elsevier.

Figure 2.

Different models of Hedgehog pathway signaling. (A) Type I ligand-independent cancers harbor inactivating mutations in Patched 1 protein (PTCH) or activating mutations in Smoothened (SMO) leading to constitutive activation of the Hedgehog (Hh) pathway even in the absence of the Hh ligand. (B) Type II ligand-dependent autocrine cancers both produce and respond to the Hh ligand leading to support tumor growth and survival. (C) Type III ligand-dependent paracrine cancers secrete the Hh ligand which is received by the stromal cells leading to pathway activation in the stroma. The stroma in turn feeds back various signals such as IGF, Wnt, VEGF to the tumor tissue leading to its growth or survival. (D) Type IIIb reverse paracrine tumors receive Hh secreted from the stroma leading to pathway activation in the tumor cells and upregulation of survival signals. (E) Cancer stem cells (CSCs): Hh signaling occurs only in the self-renewing CSCs, from the Hh ligand produced either by the CSCs or by the stroma. CSC will give rise to more Hh pathway dependent CSCs or possibly may differentiate into Hh-pathway negative tumor cells comprising the bulk of the tumor. Reprinted from: Scales, S.J. and de Sauvage, F.J. (2009) Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci 30: 303–312, with permission from Elsevier.