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Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors

Mandelin, Jami, Cardó-Vila, Marina, Driessen, Wouter H. P., Mathew, Paul, Navone, Nora M., Lin, Sue-Hwa, Logothetis, Christopher J., Rietz, Anna Cecilia, Dobroff, Andrey S., Proneth, Bettina, Sidman, Richard L., Pasqualini, Renata, Arap, Wadih
Proceedings of the National Academy of Sciences of the United States of America 2015 v.112 no.12 pp. 3776-3781
bacteriophages, drugs, metastasis, models, patients, peptides, prostatic neoplasms, receptors, therapeutics
We performed combinatorial peptide library screening in vivo on a novel human prostate cancer xenograft that is androgen-independent and induces a robust osteoblastic reaction in bonelike matrix and soft tissue. We found two peptides, PKRGFQD and SNTRVAP, which were enriched in the tumors, targeted the cell surface of androgen-independent prostate cancer cells in vitro, and homed to androgen receptor-null prostate cancer in vivo. Purification of tumor homogenates by affinity chromatography on these peptides and subsequent mass spectrometry revealed a receptor for the peptide PKRGFQD, α-2-macroglobulin, and for SNTRVAP, 78-kDa glucose-regulated protein (GRP78). These results indicate that GRP78 and α-2-macroglobulin are highly active in osteoblastic, androgen-independent prostate cancer in vivo. These previously unidentified ligand–receptor systems should be considered for targeted drug development against human metastatic androgen-independent prostate cancer.