Hedgehog Inhibition as an Anti-Cancer Strategy

G. Praveen Raju, Diane Pham

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

10 Scopus citations

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.

Original languageEnglish
Title of host publicationVitamins and Hormones
PublisherAcademic Press Inc.
Pages507-522
Number of pages16
DOIs
StatePublished - 2012
Externally publishedYes

Publication series

NameVitamins and Hormones
Volume88
ISSN (Print)0083-6729

Keywords

  • GLI
  • Hedgehog antagonists
  • Medulloblastoma
  • Smoothened
  • Sonic Hedgehog
  • Tumor stroma

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