Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands.
We have recently identified glucose-regulated protein-78 (GRP78) as a relevant molecular target expressed in metastatic tumors by fingerprinting the circulating repertoire of antibodies from cancer patients. Here we design and evaluate a ligand-receptor system based on the tumor cell membrane expression of GRP78. We show that GRP78 binding peptide motifs target tumor cells specifically in vivo and in human cancer specimens ex vivo. Moreover, synthetic chimeric peptides composed of GRP78 binding motifs fused to a programmed cell death-inducing sequence can suppress tumor growth in xenograft and isogenic mouse models of prostate and breast cancer. Together, these preclinical data validate GRP78 on the tumor cell surface as a functional molecular target that may prove useful for translation into clinical applications.
Arap
Marco A
MA
The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Lahdenranta
Johanna
J
Mintz
Paul J
PJ
Hajitou
Amin
A
Sarkis
Alvaro S
AS
Arap
Wadih
W
Pasqualini
Renata
R
D000818:Animals; D017209:Apoptosis; D002462:Cell Membrane / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018832:Molecular Chaperones / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010455:Peptides / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D011993:Recombinant Fusion Proteins; D014407:Tumor Cells, Cultured
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D008024:Ligands; D018832:Molecular Chaperones; D010455:Peptides; D011993:Recombinant Fusion Proteins