title: Inhibition of established micrometastases by targeted drug delivery via cell surface-associated GRP78.
abstract: OBJECTIVE
  The major cause of morbidity in breast cancer is development of metastatic disease, for which few effective therapies exist. Because tumor cell dissemination is often an early event in breast cancer progression and can occur before diagnosis, new therapies need to focus on targeting established metastatic disease in secondary organs. We report an effective therapy based on targeting cell surface-localized glucose-regulated protein 78 (GRP78). GRP78 is expressed normally in the endoplasmic reticulum, but many tumors and disseminated tumor cells are subjected to environmental stresses and exhibit elevated levels of GRP78, some of which are localized at the plasma membrane.
  
  
  RESULTS
  Here, we show that matched primary tumors and metastases from patients who died from advanced breast cancer also express high levels of GRP78. We used a peptidomimetic targeting strategy that uses a known GRP78-binding peptide fused to a proapoptotic moiety [designated bone metastasis targeting peptide 78 (BMTP78)] and show that it can selectively kill breast cancer cells that express surface-localized GRP78. Furthermore, in preclinical metastasis models, we show that administration of BMTP78 can inhibit primary tumor growth as well as prolong overall survival by reducing the extent of outgrowth of established lung and bone micrometastases.
  
  
  CONCLUSIONS
  The data presented here provide strong evidence that it is possible to induce cell death in established micrometastases by peptide-mediated targeting of cell surface-localized GRP in advanced breast cancers. The significance to patients with advanced breast cancer of a therapy that can reduce established metastatic disease should not be underestimated.
authors.affiliation: Metastasis Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Yu Rebecca
authors.initials: YR
authors.lastname: Miao
authors.forename: Bedrich L
authors.initials: BL
authors.lastname: Eckhardt
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cao
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ramsay
authors.forename: Robin L
authors.initials: RL
authors.lastname: Anderson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008969:Molecular Sequence Data; D061206:Neoplasm Micrometastasis / Q000517:prevention & control*; D010455:Peptides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D010455:Peptides