Src activity rises as tumors progress towards metastasis, suggesting that Src over-activation is a common trigger for metastasis. Csk is the natural negative regulator of Src family kinases. In this transgenic model, Csk expression is selectively reduced in the eye and in a patch of wing surrounded by normal tissue, resulting in localized hyperactivation of Src. The reduced Csk expression results in overgrown eyes and crumpled wings. Although the model starts with hyperactivation of Src, genetic analyses have shown that a standard ‘cassette’ of proteins involved in cell overgrowth (‘tumors’) and metastatic behavior are activated in both the eye and wing. That is, this model allows screening of a large number of targets that are involved in tumor growth and metastasis. In addition to inhibition of tumor growth, this model creates a unique opportunity to screen for compounds that prevent metastasis by novel mechanisms other than inhibition of tumor growth.

A pilot screen of a 6,500 compound commercial library has been completed. Hits that rescue the eye appearance due to overgrowth and metastasis fall into four chemical classes; structure-activity relationship investigation was conducted with purchased and synthesized compounds. 25 compounds from the four chemical classes were selected for further analysis in secondary assays; activity has been demonstrated with multiple compounds in a series of human cancer cell lines. Further proof of concept for the use of this model has been obtained from academic experiments by one of the Founders: screening of the small National Cancer Institute diversity set using this Drosophila model resulted in multiple hits that were then validated. For example, several positive compounds further inhibited proliferation of a mouse breast tumor line in vitro, and the first compound tested thus far in vivo resulted in significant reduction of metastatic lesions in the mouse lung and significantly prolonged survival.