title: Development of a biomimetic peptide derived from collagen IV with anti-angiogenic activity in breast cancer.
abstract: Breast cancer is one of the most commonly diagnosed malignancies in women. Despite the remarkable success of mammography screening and use of adjuvant systemic therapy, it is estimated that approximately 200,000 new diagnoses will be made this year and 40,000 deaths will occur due to this disease (American Cancer Society). Angiogenesis, the growth of vessels from pre-existing microvasculature, is an essential component of tumor progression and has emerged as a therapeutic modality for anti-angiogenic therapies in cancer. Here we report in vitro and in vivo findings with a 20 amino acid peptide belonging to the collagen IV family, modified to facilitate possible translation to clinical applications. The two cysteines in its natural peptide progenitor were replaced by L-α-amino-n-butyric acid, a non-natural amino acid. The modified peptide was tested in vitro using endothelial cells and in vivo using mouse orthotopic breast cancer xenograft model with MDA-MB-231 human breast cancer cells. This modified peptide demonstrated no significant changes in activity from the parent peptide; however, because it lacks cysteines, it is more suitable for clinical translation. We also investigated its efficacy in combination with a commonly used chemotherapeutic agent paclitaxel; the inhibition of tumor growth by the peptide was similar to that of paclitaxel alone, but the combination did not exhibit any additional inhibition. We have performed further characterization of the mechanism of action (MOA) for this peptide to identify its target receptors, enhancing its translation potential as an anti-angiogenic, non-vascular endothelial growth factor (VEGF) targeting agent for therapy in breast cancer.
authors: Department of Biomedical Engineering; School of Medicine, Johns Hopkins University, Baltimore, MD, USA. e.v.rosca@gmail.com
authors: Elena V
authors: EV
authors: Rosca
authors: Jacob E
authors: JE
authors: Koskimaki
authors: Niranjan B
authors: NB
authors: Pandey
authors: Antonio C
authors: AC
authors: Wolff
authors: Aleksander S
authors: AS
authors: Popel
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D032701:Biomimetics; D001943:Breast Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D024141:Collagen Type IV / Q000737:chemistry*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011956:Receptors, Cell Surface; D014945:Wound Healing / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D024141:Collagen Type IV; D010455:Peptides; D011956:Receptors, Cell Surface; C573661:SP2012