We thank our colleagues in the Department of Surgery at Mount Sinai Hospital; Dr. Qingxia Wei, Chang Ye Yale Wang, and Heather Whetstone (Program in Developmental and Stem Cell Biology, Hospital for Sick Children); Dr. Nalan Gokgoz (Lunenfeld-Tanenbaum Research Institute) for technical support; and Marisa Peluso (Infinity Pharmaceuticals, Inc.) for performing the SHH and IPI-926 treatments in MG-63.
Involvement and targeted intervention of dysregulated Hedgehog signaling in osteosarcoma
Version of Record online: 21 OCT 2013
© 2013 American Cancer Society
Volume 120, Issue 4, pages 537–547, 15 February 2014
How to Cite
Lo, W. W., Wunder, J. S., Dickson, B. C., Campbell, V., McGovern, K., Alman, B. A. and Andrulis, I. L. (2014), Involvement and targeted intervention of dysregulated Hedgehog signaling in osteosarcoma. Cancer, 120: 537–547. doi: 10.1002/cncr.28439
Infinity Pharmaceuticals, Inc., provided saridegib, performed the GLI1 immunofluorescence assay and the Shh and IPI-926 treatments in MG-63 cells, interpreted data, and was involved in preparation of the article. However, Infinity Pharmaceuticals, Inc., did not provide additional financial support beyond this and was not involved in designing the studies, collecting samples, or drawing conclusions.
- Issue online: 4 FEB 2014
- Version of Record online: 21 OCT 2013
- Manuscript Accepted: 18 SEP 2013
- Manuscript Revised: 16 SEP 2013
- Manuscript Received: 23 APR 2013
- hedgehog signaling;
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.
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.
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.
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. Cancer 2014;120:537–547. © 2013 American Cancer Society.