title: Therapeutic inhibition of breast cancer bone metastasis progression and lung colonization: breaking the vicious cycle by targeting α5β1 integrin.
abstract: At diagnosis, 10 % of breast cancer patients already have locally advanced or metastatic disease; moreover, metastasis eventually develops in at least 40 % of early breast cancer patients. Osteolytic bone colonization occurs in 80-85 % of metastatic breast cancer patients and is thought to be an early step in metastatic progression. Thus, breast cancer displays a strong preference for metastasis to bone, and most metastatic breast cancer patients will experience its complications. Our prior research has shown that the α5β1 integrin fibronectin receptor mediates both metastatic and angiogenic invasion. We invented a targeted peptide inhibitor of activated α5β1, Ac-PHSCN-NH2 (PHSCN), as a validated lead compound to impede both metastatic invasion and neovascularization. Systemic PHSCN monotherapy prevented disease progression for up to 14 months in Phase I clinical trial. Here, we report that the next-generation construct, Ac-PhScN-NH2 (PhScN), which contains D-isomers of histidine (h) and cysteine (c), is greater than 100,000-fold more potent than PHSCN at blocking basement membrane invasion. Moreover, PhScN is also up to 10,000-fold more potent than PHSCN at inhibiting lung extravasation and colonization in athymic mice for both MDA-MB-231 metastatic and SUM149PT inflammatory breast cancer cells. Furthermore, we show that systemic treatment with 50 mg/kg PhScN monotherapy reduces established intratibial MDA-MB-231 bone colony progression by 80 %. Thus, PhScN is a highly potent, well-tolerated inhibitor of both lung colonization and bone colony progression.
authors.affiliation: Department of Radiation Oncology and Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-5637, USA.
authors.forename: Hongren
authors.initials: H
authors.lastname: Yao
authors.affiliation: Department of Radiation Oncology and Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-5637, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Veine
authors.affiliation: Department of Radiation Oncology and Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-5637, USA. dlivant@umich.edu.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Livant
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D039081:Integrin alpha5beta1; D009842:Oligopeptides; C404392:acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide
keywords: Bone metastasis; Breast cancer; Extravasation; Integrin fibronectin receptor; Invasion; Lung metastasis; Systemic therapy