In response to an urgent need for improved diagnostic and predictive serum biomarkers for management of metastatic prostate cancer, we used phage display fingerprinting to analyze sequentially acquired serum samples from a patient with advancing prostate cancer. We identified a peptide ligand, CTFAGSSC, demonstrating an increased recovery frequency over time. Serum antibody reactivity to this peptide epitope increased in the index patient, in parallel with development of deteriorating symptoms. The antigen mimicking the peptide epitope was identified as alpha-2-HeremansSchmid glycoprotein, also known as fetuin-A. Metastatic prostate cancer cell lines and bone metastasis samples displayed robust fetuin-A expression, and we demonstrated serum immune reactivity to fetuin-A with concomitant development of metastatic castrateresistant disease in a large cohort of prostate cancer patients. Whereas fetuin-A is an established tumor antigen in several types of cancer, including breast cancer, glioblastoma, and pancreas cancer, this report is to our knowledge the first study implicating fetuin-A in prostate cancer and indicating that autoantibodies specific for fetuin-A show utility as a prognostic indicator for prostate cancer patients prone to progress to metastatic disease.cancer biomarker | peptide library | prostate cancer | phage display
We performed combinatorial peptide library screening in vivo on a novel human prostate cancer xenograft that is androgenindependent 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.peptides | ligand receptors | phage display | GRP78 | tumor targeting A ndrogen deprivation remains the standard therapy for metastatic prostate cancer. Despite the favorable initial response, in most cases the disease progresses, becomes androgen-independent, and gives rise to soft tissue and osteoblastic bone metastases that ultimately lead to death (1, 2). Paradoxically, all currently available animal models of osteoblastic bone metastases are androgen dependent (3-6). The first (to our knowledge) human prostate cancer xenograft model that does not express androgen receptor but still induces a strong osteogenic response led Li et al. (7) to conclude that androgen receptor-null cells contribute to the castrate-resistant osteoblastic progression of prostate cancer and that targeting these cells will be critical in the treatment of prostate cancer bone metastases.In vivo phage display can be used to explore the surface of cells in their anatomical microenvironment (8)(9)(10)(11)(12)(13)(14). This technology enables the identification of molecular signatures that could allow targeted systemic delivery of therapeutic agents to cancer tissues (9,12,15,16). Using such methodology and the special prostate cancer model (7), we hypothesized that ligandreceptor pairs for targeting metastasizing androgen-independent prostate cancer cells could be identified.Here we select two novel ligand peptides that were selected in vivo from human androgen-independent prostate cancer xenografts. We show that they target the surface of an androgenindependent prostatic cell line in vitro and home to androgen receptor-null prostate tumors in vivo. With affinity chromatography, we next isolated their respective receptors, 78-kDa glucose-regulated protein (GRP78) and α-2-macroglobulin, from tumor lysates and as a proof of principle verified the peptide-GRP78 interaction in vitro with recombinant GRP78. These data confirm that GRP78 is a functional molecular target on prostatic cancer cell surfaces in vivo. Such ligand-receptor systems may be applicable to targeted therapy and should be...
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