COMPOSITIONS AND METHODS FOR MODULATING SIGNALING MEDIATED BY IGF-1 RECEPTOR AND ERBB RECEPTORS

摘要

The binding interactions between herstatin, or the intron 8-encoded receptorbinding domain (RBD Int8) thereof, and several receptors were analyzed.According to aspects of the present invention, herstatin and the intron 8-encoded domain bind with high affinity (e.g., nM concentrations) to all fourof the ErbB receptors: EGFR (HER-1, erbB-1); HER-2 (erbB-2); HER-3 (erbB-3);and HER-4 (erbB-4), as well as to .DELTA.EGFR and the IGF-1 receptor, and suchbinding has utility to modulate signaling mediated by these receptors.Herstatin inhibited target receptor-mediated activation of intracellularsignaling pathways ((e.g., PI3/Akt, IRS-2, etc., pathways) that are importantin cell survival, and further inhibited target receptor-mediated (e.g., IGF-1/IGF-1R-mediated) survival of cancer cells. Aspects of the present inventionthus provide methods and compositions for the treatment of cancer, includingcancer refractory to other erbB-based agents, and of other conditions anddisorders characterized by target receptor expression, over-expression,signaling, and/or aberrant signaling. Additional aspects provide methods oftargeted drug delivery.