Hedgehog Inhibition as an Anti-Cancer Strategy

Abstract

Dysregulated Hedgehog (Hh) signaling has been implicated in a growing number of human cancers. Although first identified as an important developmental signaling pathway crucial for cellular proliferation, differentiation, and migration during organogenesis in invertebrates, these fundamental processes have been co-opted in human cancers. Initial evidence for the Hh pathway in tumor biology comes from mutations of signaling pathway components in a hereditary cancer syndrome that typically results in basal-cell carcinoma and medulloblastoma. Subsequent analysis revealed that Hh pathway mutations are found in sporadic tumors as well as activated Hh signaling in several epithelial cancers independent of Hh pathway mutation status. Further, recent evidence has demonstrated paracrine Hh signaling within stromal cells of the tumor microenvironment with implications for drug delivery. Several Hh antagonists targeting the Hh receptor, Smoothened (SMO), have been developed and show efficacy in preclinical studies and early-stage clinical trials in humans. However, major issues with these small molecule compounds include rapid acquired resistance, potential developmental toxicities secondary to use in children, and limited efficacy in cancers driven by Hh signaling downstream of the SMO receptor.

Introduction

The secreted signaling molecule, Hedgehog (Hh), and several components of its signal transduction pathway were initially identified secondary to their roles in early embryonic patterning through classical genetic mutagenesis screens in Drosophila (Nusslein-Volhard and Wieschaus, 1980). Subsequent analysis has revealed that most of the components of the pathway are conserved in higher organisms, including humans. Although the Hh signal transduction pathway has been described in detail in other chapters of this volume and in recent reviews (Ingham et al., 2011; Ng and Curran, 2011), the pathway in vertebrates will be summarized here as an introduction to this chapter that describes the dysregulation of Hh signaling in various cancers as well as within stromal cells of the tumor microenvironment.

In brief, Hh ligands bind to a 12-pass transmembrane receptor, Patched 1 (PTCH1), a negative regulator of the pathway, that results in its internalization and subsequent degradation. This results in release of the negative influence of PTCH1 on the 16-pass transmembrane protein, Smoothened (SMO), which then can enter the primary cilia through a poorly understood mechanism. Activated SMO then promotes dissociation of a Suppressor of fused (SUFU)-glioma associated oncogene homolog (GLI) protein complex that results in alterations in proteolytic processing of GLI proteins. This results in nuclear translocation and activation of the GLI2 transcription factor and degradation of the repressor, GLI3. The activated GLI2 protein stimulates the transcription of Hh pathway target genes, many of which are critical for important processes including cell proliferation, differentiation, and migration. Normally, the precise timing and duration of Hh signaling results in proper embryonic patterning as well as tissue differentiation during organogenesis (McMahon et al., 2003). However, alterations of the Hh pathway, primarily through mutations of pathway components or through mechanisms that result in upregulated GLI transcriptional activity, often result in dysregulated cell proliferation thus resulting in cancer.