TGF-beta-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases.

Abstract

Melanoma often metastasizes to bone where it is exposed to high concentrations of TGF-β. Constitutive Smad signaling occurs in human melanoma. Because TGF-β promotes metastases to bone by several types of solid tumors including breast cancer, we hypothesized that pharmacologic blockade of the TGF-β signaling pathway may interfere with the capacity of melanoma cells to metastasize to bone. In this study, we tested the effect of a small molecule inhibitor of TGF-β receptor I kinase (TβRI), SD-208, on various parameters affecting the development and progression of melanoma, both in vitro and in a mouse model of human melanoma bone metastasis. In melanoma cell lines, SD-208 blocked TGF-β induction of Smad3 phosphorylation, Smad3/4-specific transcription, Matrigel invasion and expression of the TGF-β target genes PTHrP, IL-11, CTGF, and RUNX2. To assess effects of SD-208 on melanoma development and metastasis, nude mice were inoculated with 1205Lu melanoma cells into the left cardiac ventricle and drug was administered by oral gavage on prevention or treatment protocols. SD-208 (60 mg/kg/d), started 2 days before tumor inoculation prevented the development of osteolytic bone metastases compared with vehicle. In mice with established bone metastases, the size of osteolytic lesions was significantly reduced after 4 weeks treatment with SD-208 compared with vehicle-treated mice. Our results demonstrate that therapeutic targeting of TGF-β may prevent the development of melanoma bone metastases and decrease the progression of established osteolytic lesions.

• Authors: Khalid S Mohammad, Delphine Javelaud, Pierrick G J Fournier, Maria Niewolna, C Ryan McKenna, Xiang H Peng, Vu Duong, Lauren K Dunn, Alain Mauviel, Theresa A Guise
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 1 Pg. 175-84 (Jan 01 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21084275 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2010 AACR.

Chemical References

• DNA Primers
• Protein Kinase Inhibitors
• Pteridines
• Receptors, Transforming Growth Factor beta
• SD-208
• Smad Proteins

Topics

• Animals
• Base Sequence
• Bone Neoplasms (prevention & control, secondary)
• Cell Line, Tumor
• DNA Primers
• Disease Models, Animal
• Disease Progression
• Gene Expression Profiling
• Humans
• Melanoma (pathology)
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Pteridines (pharmacology)
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors)
• Smad Proteins (metabolism)