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

Significance This study shows how phage display technology can be applied successfully to in vivo models and can advance molecular oncology through the identification of tumor-homing peptides and their target receptors. Treatment options are still limited for prostate cancer patients who have progressed to develop castrate-resistant osteoblastic bone metastases. The peptides identified in this study may lead to breakthroughs in fighting metastatic androgen-independent prostate cancer by enabling drug targeting and nanotechnology-based therapeutic strategies and may lead to significant advances in the management and therapy of this frequently lethal disease. 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.