Experimental and bioinformatic analysis of endogenous and mimetic anti-angiogenic peptides in application to cancer

After identification of a computational methodology to identify short purported anti-angiogenic motifs in the human proteome, we began experimental screening of these peptide fragments to show anti-angiogenic activity in vitro and in vivo. The identification of >120 novel endogenous peptide inhibitors come from diverse families such as thrombospondin-1 domain containing families, CXC chemokines, type IV collagen, serpins and somatotropins. We show here in vivo activity in small cell lung cancer (SCLC) and triple negative breast cancer xenograft models, as well as creation of peptidomimetics from type IV collagen. Peptides applied in combination to angiogenesis-dependent diseases have the potential to limit vessel growth through inhibition of multiple signaling pathways and creating an enhanced synergistic response. Experimental screening described in our studies shows a type IV collagen mimetic peptide synergizes in vitro and in vivo with a somatotropin domain-containing peptide through inhibition of vascular endothelial growth factor (VEGF) pathways and focal adhesion kinase (FAK). Further bioinformatic analysis highlights key pathways in addition to VEGF-based pathways responsible for this effect.;As angiogenesis is central to over 70 pathologies and anti-angiogenic therapies have been estimated to benefit millions in the upcoming decades, short peptide-based therapies applied as monotherapy or in combination have the potential to suppress tumor growth and other diseases. The experimental and bioinformatics screening described in this dissertation demonstrate the potential of anti-angiogenic peptides in application to cancer.