Involvement and targeted intervention of dysregulated Hedgehog signaling in osteosarcoma.

Abstract

BACKGROUND:

During development, the Hedgehog pathway plays important roles regulating the proliferation and differentiation of chondrocytes, providing a template for growing bone. In this study, the authors investigated the components of dysregulated Hedgehog signaling as potential therapeutic targets for osteosarcoma.

METHODS:

Small-molecule agonists and antagonists that modulate the Hedgehog pathway at different levels were used to investigate the mechanisms of dysregulation and the efficacy of Hedgehog blockade in osteosarcoma cell lines. The inhibitory effect of a small-molecule Smoothened (SMO) antagonist, IPI-926 (saridegib), also was examined in patient-derived xenograft models.

RESULTS:

An inverse correlation was identified in osteosarcoma cell lines between endogenous glioma-associated oncogene 2 (GLI2) levels and Hedgehog pathway induction levels. Cells with high levels of GLI2 were sensitive to GLI inhibition, but not SMO inhibition, suggesting that GLI2 overexpression may be a mechanism of ligand-independent activation. In contrast, cells that expressed high levels of the Hedgehog ligand gene Indian hedgehog (IHH) and the target genes patched 1 (PTCH1) and GLI1 were sensitive to modulation of both SMO and GLI, suggesting ligand-dependent activation. In 2 xenograft models, active autocrine and paracrine, ligand-dependent Hedgehog signaling was identified. IPI-926 inhibited the Hedgehog signaling interactions between the tumor and the stroma and demonstrated antitumor efficacy in 1 of 2 ligand-dependent models.

CONCLUSIONS:

The current results indicate that both ligand-dependent and ligand-independent Hedgehog dysregulation may be involved in osteosarcoma. It is the first report to demonstrate Hedgehog signaling crosstalk between the tumor and the stroma in osteosarcoma. The inhibitory effect of IPI-926 warrants additional research and raises the possibility of using Hedgehog pathway inhibitors as targeted therapeutics to improve treatment for osteosarcoma.

• Authors: Winnie W Lo, Jay S Wunder, Brendan C Dickson, Veronica Campbell, Karen McGovern, Benjamin A Alman, Irene L Andrulis
• Journal: Cancer (Cancer) Vol. 120 Issue 4 Pg. 537-47 (Feb 15 2014) ISSN: 1097-0142 [Electronic] United States
• PMID: 24151134 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 American Cancer Society.

Chemical References

• Antineoplastic Agents
• GLI1 protein, human
• GLI2 protein, human
• Hedgehog Proteins
• IPI-926
• Kruppel-Like Transcription Factors
• Nuclear Proteins
• Receptors, G-Protein-Coupled
• SMO protein, human
• Smoothened Receptor
• Transcription Factors
• Veratrum Alkaloids
• Zinc Finger Protein GLI1
• Zinc Finger Protein Gli2

Topics

• Adolescent
• Adult
• Antineoplastic Agents (administration & dosage)
• Bone Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Child
• Female
• Hedgehog Proteins (genetics, metabolism)
• Humans
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Male
• Molecular Targeted Therapy
• Nuclear Proteins (genetics, metabolism)
• Osteosarcoma (drug therapy, etiology, genetics, pathology)
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Signal Transduction (drug effects)
• Smoothened Receptor
• Transcription Factors (genetics, metabolism)
• Veratrum Alkaloids (administration & dosage)
• Xenograft Model Antitumor Assays
• Zinc Finger Protein GLI1
• Zinc Finger Protein Gli2