This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Giubellino, A. Articles by Bottaro, D. P. Search for Related Content PubMed PubMed Citation Articles by Giubellino, A. Articles by Bottaro, D. P.

Inhibition of Tumor Metastasis by a Growth Factor Receptor Bound Protein 2 Src Homology 2 Domain–Binding Antagonist

¹ Urologic Oncology Branch, ² Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland; and ³ Laboratory of Medicinal Chemistry, National Cancer Institute, Frederick, Maryland

Requests for reprints: Donald P. Bottaro, Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10, CRC 1 West, Room 3961, 10 Center Drive, MSC 1107, Bethesda, MD 20892-1107. Phone: 301-402-6499; Fax: 301-402-0922; E-mail: dbottaro{at}helix.nih.gov.

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. [Cancer Res 2007;67(13):6012–6]