Inhibition of tumor metastasis by a growth factor receptor bound protein 2 Src homology 2 domain-binding antagonist.
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.
Giubellino
Alessio
A
Urologic Oncology Branch, Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892-1107, USA.
Gao
Yang
Y
Lee
Sunmin
S
Lee
Min-Jung
MJ
Vasselli
James R
JR
Medepalli
Sampath
S
Trepel
Jane B
JB
Burke
Terrence R
TR
Bottaro
Donald P
DP
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue