Involvement and targeted intervention of dysregulated Hedgehog signaling in osteosarcoma. Issue 4 (21st October 2013)

• Record Type: Journal Article
• Authors: Lo, Winnie W.; Wunder, Jay S.; Dickson, Brendan C.; Campbell, Veronica; McGovern, Karen; Alman, Benjamin A.; Andrulis, Irene L.
• Is Part Of: Cancer. Volume 120:Issue 4(2014)
• Page Start: 537
• Page End: 547
• Publication Date: 2013-10-21
• Subjects: Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.28439
• Languages: English
• ISSNs: 0008-543X

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="cncr28439-sec-0001" sec-type="section"> <title>BACKGROUND</title> <p>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.</p> </sec> <sec id="cncr28439-sec-0002" sec-type="section"> <title>METHODS</title> <p>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.</p> </sec> <sec id="cncr28439-sec-0003" sec-type="section"> <title>RESULTS</title> <p>An inverse correlation was identified in osteosarcoma cell lines between endogenous glioma‐associated oncogene 2 (<italic>GLI2</italic>) levels and Hedgehog pathway induction levels. Cells with high levels of <italic>GLI2</italic> were sensitive to GLI inhibition, but not SMO inhibition, suggesting that <italic>GLI2</italic> overexpression may be a mechanism of ligand‐independent activation. In contrast, cells that expressed high levels of the Hedgehog ligand gene Indian hedgehog (<italic>IHH</italic>) and the target genes patched 1 (<italic>PTCH1</italic>) and <italic>GLI1</italic> 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.</p> </sec> <sec id="cncr28439-sec-0004" sec-type="section"> <title>CONCLUSIONS</title> <p>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. <bold><italic>Cancer</italic> 2014;120:537–547</bold>. © <italic>2013 American Cancer Society</italic>.</p> </sec> </abstract>