Harnessing Novel Secreted Inhibitors of EGF Receptor Signaling for Breast Cancer Treatment
Annual rept. 7 Mar 2005-6 Mar 2006
PENNSYLVANIA UNIV PHILADELPHIA
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The aim of our research is to develop protein therapeutics that can neutralize the growth factors that activate members of the EGF receptor family in breast cancer. Whereas other agents that target this receptor system target the receptor itself eg. Herceptin, Iressa,we propose to target the activating ligand. Our model is the protein Argos from Drosophila,which we discovered inhibits EGF receptor signaling naturally in the fruit fly by inactivating the ligand. Our goal, in effect, is to humanize Argos by making it bind human EGF receptor ligands and to use a human protein scaffold to do so. In the past year, we have identified the minimum fragment of Argos 218 amino acids required for its function, and have identified two loops that contribute to its ligand binding site. We have also grown crystals, and anticipate determining a high resolution structure in the next year. We have found that our human structural scaffolds Dickkopf proteins do not bind human EGFs. Our next step is to take the important structurefunction information obtained in the past year,and apply it as we screen in phage display for Argos and Dkk variants that bind human EGFs.
- Medicine and Medical Research