Harnessing Novel Secreted Inhibitors of EGF Receptor Signaling for Breast Cancer Treatment; Final rept. 7 Mar 2005-6 Mar 2008

摘要

We aim to develop protein therapeutics that neutralizes growth factors that activate EGF receptor family members in breast cancer. Rather than targeting receptors themselves (as do Herceptin, Iressa, etc), we propose to target the activating ligands. Our model is Argos from Drosophila, which we showed naturally, inhibits EGF receptor signaling in fruit flies by inactivating the ligand. We hope to effectively humanize Argos - making it bind human EGFR ligands and/or to use human protein scaffolds for this. In the past year, we crystallized a complex between the minimal functional fragment of Argos and its target (Spitz), and are about to complete structure determination which will provide critical information for therapeutic design. We also established an experimental approach for screening libraries of Argos variants for those that bind human EGF-like ligands (our therapeutic aim). This approach employs yeast surface (rather than phage) display. We are now poised to combine our technical position and new structural information to identify Argos (and Dkk) variants that bind human EGFs and represent starting points for developing new therapeutics.