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 progre...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2015-03, Vol.112 (12), p.3776-3781 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1073/pnas.1500128112 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1500128112</identifier><identifier>PMID: 25762070</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>alpha-Macroglobulins - metabolism ; Animals ; bacteriophages ; Biological Sciences ; Bone Neoplasms - secondary ; Cell Line, Tumor ; Chromatography ; Chromatography, Affinity ; Disease Progression ; Drug Design ; Drug Screening Assays, Antitumor ; drugs ; Heat-Shock Proteins - metabolism ; Humans ; Ligands ; Male ; Mass spectrometry ; Medical screening ; metastasis ; Mice ; Mice, SCID ; Nanotechnology ; Neoplasm Transplantation ; Osteogenesis ; patients ; Peptides ; Peptides - chemistry ; Prostate cancer ; prostatic neoplasms ; Prostatic Neoplasms, Castration-Resistant - drug therapy ; Prostatic Neoplasms, Castration-Resistant - metabolism ; Prostatic Neoplasms, Castration-Resistant - pathology ; Protein Binding ; Proteomics ; receptors ; Receptors, Androgen - metabolism ; Skin & tissue grafts ; therapeutics</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2015-03, Vol.112 (12), p.3776-3781</ispartof><rights>Volumes 1–89 and 106–112, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Mar 24, 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c557t-dff91bcddb8fe1ba835994501b235f9bfcf4ee061964362f5dcbaf0c0bd032a03</citedby><cites>FETCH-LOGICAL-c557t-dff91bcddb8fe1ba835994501b235f9bfcf4ee061964362f5dcbaf0c0bd032a03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/112/12.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26462154$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26462154$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25762070$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mandelin, Jami</creatorcontrib><creatorcontrib>Cardó-Vila, Marina</creatorcontrib><creatorcontrib>Driessen, Wouter H. P.</creatorcontrib><creatorcontrib>Mathew, Paul</creatorcontrib><creatorcontrib>Navone, Nora M.</creatorcontrib><creatorcontrib>Lin, Sue-Hwa</creatorcontrib><creatorcontrib>Logothetis, Christopher J.</creatorcontrib><creatorcontrib>Rietz, Anna Cecilia</creatorcontrib><creatorcontrib>Dobroff, Andrey S.</creatorcontrib><creatorcontrib>Proneth, Bettina</creatorcontrib><creatorcontrib>Sidman, Richard L.</creatorcontrib><creatorcontrib>Pasqualini, Renata</creatorcontrib><creatorcontrib>Arap, Wadih</creatorcontrib><title>Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>alpha-Macroglobulins - metabolism</subject><subject>Animals</subject><subject>bacteriophages</subject><subject>Biological Sciences</subject><subject>Bone Neoplasms - secondary</subject><subject>Cell Line, Tumor</subject><subject>Chromatography</subject><subject>Chromatography, Affinity</subject><subject>Disease Progression</subject><subject>Drug Design</subject><subject>Drug Screening Assays, Antitumor</subject><subject>drugs</subject><subject>Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Ligands</subject><subject>Male</subject><subject>Mass spectrometry</subject><subject>Medical screening</subject><subject>metastasis</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Nanotechnology</subject><subject>Neoplasm Transplantation</subject><subject>Osteogenesis</subject><subject>patients</subject><subject>Peptides</subject><subject>Peptides - chemistry</subject><subject>Prostate cancer</subject><subject>prostatic neoplasms</subject><subject>Prostatic Neoplasms, Castration-Resistant - drug therapy</subject><subject>Prostatic Neoplasms, Castration-Resistant - metabolism</subject><subject>Prostatic Neoplasms, Castration-Resistant - pathology</subject><subject>Protein Binding</subject><subject>Proteomics</subject><subject>receptors</subject><subject>Receptors, Androgen - metabolism</subject><subject>Skin & tissue grafts</subject><subject>therapeutics</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkk2LFDEQhoMo7jh69qQ2ePHSu5Xv7suCLH7Bgod1zyGdTnoz9HTaJCP4B_zdpnfGGfWiEAhJPfVWqvIi9BzDOQZJL-ZJp3PMATBpMCYP0ApDi2vBWniIVgBE1g0j7Aw9SWkDAC1v4DE6I1wKAhJW6MeNHa3JPkyVnvrK93bK3nmj76-Cq0Y_LIHZzrkEU5V1HGz201Dpaht6Oy6Q0SlHnW0dbfIp6ylXIWUbBjt5U82xHEq0YJOx8b5QvrM-VtGaohtieooeOT0m--ywr9Ht-3dfrj7W158_fLp6e10bzmWue-da3Jm-7xpncacbytuWccAdody1nTOOWQsCt4JRQRzvTacdGOh6oEQDXaPLve6867a2N6XbqEc1R7_V8bsK2qs_I5O_U0P4phiVZZBNEXhzEIjh686mrLY-GTuOerJhlxRugELLpJT_RoUUlHPB-X-gQrSNKGxBX_-FbsIuTmVoCyUZL80vtS_2lCmzT9G6Y4sY1OIctThHnZxTMl7-Ppkj_8sqBXh1AJbMoxwmqiwqSy9r9GJPbFL505OCYIJgzk4KTgelh-iTur0hgEV5BFu8SX8CP5zflA</recordid><startdate>20150324</startdate><enddate>20150324</enddate><creator>Mandelin, Jami</creator><creator>Cardó-Vila, Marina</creator><creator>Driessen, Wouter H. 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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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c557t-dff91bcddb8fe1ba835994501b235f9bfcf4ee061964362f5dcbaf0c0bd032a03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>alpha-Macroglobulins - metabolism</topic><topic>Animals</topic><topic>bacteriophages</topic><topic>Biological Sciences</topic><topic>Bone Neoplasms - secondary</topic><topic>Cell Line, Tumor</topic><topic>Chromatography</topic><topic>Chromatography, Affinity</topic><topic>Disease Progression</topic><topic>Drug Design</topic><topic>Drug Screening Assays, Antitumor</topic><topic>drugs</topic><topic>Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Ligands</topic><topic>Male</topic><topic>Mass spectrometry</topic><topic>Medical screening</topic><topic>metastasis</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Nanotechnology</topic><topic>Neoplasm Transplantation</topic><topic>Osteogenesis</topic><topic>patients</topic><topic>Peptides</topic><topic>Peptides - chemistry</topic><topic>Prostate cancer</topic><topic>prostatic neoplasms</topic><topic>Prostatic Neoplasms, Castration-Resistant - drug therapy</topic><topic>Prostatic Neoplasms, Castration-Resistant - metabolism</topic><topic>Prostatic Neoplasms, Castration-Resistant - pathology</topic><topic>Protein Binding</topic><topic>Proteomics</topic><topic>receptors</topic><topic>Receptors, Androgen - metabolism</topic><topic>Skin & tissue grafts</topic><topic>therapeutics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mandelin, Jami</creatorcontrib><creatorcontrib>Cardó-Vila, Marina</creatorcontrib><creatorcontrib>Driessen, Wouter H. P.</creatorcontrib><creatorcontrib>Mathew, Paul</creatorcontrib><creatorcontrib>Navone, Nora M.</creatorcontrib><creatorcontrib>Lin, Sue-Hwa</creatorcontrib><creatorcontrib>Logothetis, Christopher J.</creatorcontrib><creatorcontrib>Rietz, Anna Cecilia</creatorcontrib><creatorcontrib>Dobroff, Andrey S.</creatorcontrib><creatorcontrib>Proneth, Bettina</creatorcontrib><creatorcontrib>Sidman, Richard L.</creatorcontrib><creatorcontrib>Pasqualini, Renata</creatorcontrib><creatorcontrib>Arap, Wadih</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mandelin, Jami</au><au>Cardó-Vila, Marina</au><au>Driessen, Wouter H. P.</au><au>Mathew, Paul</au><au>Navone, Nora M.</au><au>Lin, Sue-Hwa</au><au>Logothetis, Christopher J.</au><au>Rietz, Anna Cecilia</au><au>Dobroff, Andrey S.</au><au>Proneth, Bettina</au><au>Sidman, Richard L.</au><au>Pasqualini, Renata</au><au>Arap, Wadih</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2015-03-24</date><risdate>2015</risdate><volume>112</volume><issue>12</issue><spage>3776</spage><epage>3781</epage><pages>3776-3781</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>25762070</pmid><doi>10.1073/pnas.1500128112</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | alpha-Macroglobulins - metabolism Animals bacteriophages Biological Sciences Bone Neoplasms - secondary Cell Line, Tumor Chromatography Chromatography, Affinity Disease Progression Drug Design Drug Screening Assays, Antitumor drugs Heat-Shock Proteins - metabolism Humans Ligands Male Mass spectrometry Medical screening metastasis Mice Mice, SCID Nanotechnology Neoplasm Transplantation Osteogenesis patients Peptides Peptides - chemistry Prostate cancer prostatic neoplasms Prostatic Neoplasms, Castration-Resistant - drug therapy Prostatic Neoplasms, Castration-Resistant - metabolism Prostatic Neoplasms, Castration-Resistant - pathology Protein Binding Proteomics receptors Receptors, Androgen - metabolism Skin & tissue grafts therapeutics |
| title | Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors |
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