Inhibition of tumor metastasis by a growth factor receptor bound protein 2 Src homology 2 domain-binding antagonist.

Abstract	Metastasis, the primary cause of death in most forms of cancer, is a multistep process whereby cells from the primary tumor spread systemically and colonize distant new sites. Blocking critical steps in this process could potentially inhibit tumor metastasis and dramatically improve cancer survival rates; however, our understanding of metastasis at the molecular level is still rudimentary. Growth factor receptor binding protein 2 (Grb2) is a widely expressed adapter protein with roles in epithelial cell growth and morphogenesis, as well as angiogenesis, making it a logical target for anticancer drug development. We have previously shown that a potent antagonist of Grb2 Src homology-2 domain-binding, C90, blocks growth factor-driven cell motility in vitro and angiogenesis in vivo. We now report that C90 inhibits metastasis in vivo in two aggressive tumor models, without affecting primary tumor growth rate. These results support the potential efficacy of this compound in reducing the metastatic spread of primary solid tumors and establish a critical role for Grb2 Src homology-2 domain-mediated interactions in this process.
Authors	Alessio Giubellino, Yang Gao, Sunmin Lee, Min-Jung Lee, James R Vasselli, Sampath Medepalli, Jane B Trepel, Terrence R Burke Jr, Donald P Bottaro
Journal	Cancer research (Cancer Res) Vol. 67 Issue 13 Pg. 6012-6 (Jul 01 2007) ISSN: 0008-5472 [Print] United States
PMID	17616655 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References	GRB2 Adaptor Protein GRB2 protein, human Tetrazolium Salts Thiazoles thiazolyl blue
Topics	Animals Cell Line, Tumor Cell Movement Cell Proliferation GRB2 Adaptor Protein (antagonists & inhibitors, metabolism, physiology) Gene Expression Regulation, Neoplastic Humans Mice Mice, SCID Microscopy, Fluorescence Neoplasm Metastasis Neoplasm Transplantation Protein Binding Protein Structure, Tertiary Tetrazolium Salts (pharmacology) Thiazoles (pharmacology)

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