Antitumor Effects and Biomarkers of Activity of AZD0530, a Src Inhibitor, in Pancreatic Cancer
Purpose: To determine the efficacy of AZD0530, an orally active small molecule Src inhibitor, in human pancreatic cancer xenografts and to seek biomarkers predictive of activity. Experimental Design: Sixteen patient-derived pancreatic cancer xenografts from the PancXenoBank collection at Johns Hopki...
Gespeichert in:
| Veröffentlicht in: | Clinical cancer research 2009-06, Vol.15 (12), p.4138-4146 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 4146 |
|---|---|
| container_issue | 12 |
| container_start_page | 4138 |
| container_title | Clinical cancer research |
| container_volume | 15 |
| creator | Rajeshkumar, N V Tan, Aik Choon De Oliveira, Elizabeth Womack, Chris Wombwell, Helen Morgan, Shethah Warren, Madhuri V Walker, Jill Green, Tim P Jimeno, Antonio Messersmith, Wells A Hidalgo, Manuel |
| description | Purpose: To determine the efficacy of AZD0530, an orally active small molecule Src inhibitor, in human pancreatic cancer xenografts
and to seek biomarkers predictive of activity.
Experimental Design: Sixteen patient-derived pancreatic cancer xenografts from the PancXenoBank collection at Johns Hopkins were treated with
AZD0530 (50 mg/kg/day, p.o.) for 28 days. Baseline gene expression profiles of differently expressed genes in 16 tumors by
Affymetrix U133 Plus 2.0 gene array were used to predict AZD0530 sensitivity in an independent group of eight tumors using
the K-Top Scoring Pairs ( K-TSP ) method.
Results: Three patient tumors of 16 were found to be sensitive to AZD0530, defined as tumor growth |
| doi_str_mv | 10.1158/1078-0432.CCR-08-3021 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_67378452</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>67378452</sourcerecordid><originalsourceid>FETCH-LOGICAL-c388t-36673f1ee74a370a7fe053882f9a3c4b9e1e10f3feffcd52341af2f8c9561aa93</originalsourceid><addsrcrecordid>eNpFkMlOwzAQhi0EYik8AsgnJCQCnjhOnGMJq4QEYrlwwHLdMTW0CdguqG-PuyBO8x_-RfMRsg_sBEDIU2CVzFjB85OmeciYzDjLYY1sgxBVxvNSrCf959kiOyG8MwYFsGKTbEEtWA0l2yav_Ta6OJ10nl5YiyYGqtshPXPdRPsP9IF2lvZNdN8uzhb65ZwJzo6ppo_e0Jt25AYudv6Yupbe69Z41NEZ2iSJfpdsWD0OuLe6PfJ8efHUXGe3d1c3Tf82M1zKmPGyrLgFxKrQvGK6sphGpMxtrbkpBjUCArPcorVmKHJegLa5laYWJWhd8x45XPZ--u5riiGqiQsGx2PdYjcNKtVXskjBHhFLo_FdCB6t-vQuvTpTwNQcrJpDU3NoKoFVTKo52JQ7WA1MBxMc_qdWJJPhaGkYubfRj_OozIKAx4Dam5ECoSBXBXDJfwEjSoDQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>67378452</pqid></control><display><type>article</type><title>Antitumor Effects and Biomarkers of Activity of AZD0530, a Src Inhibitor, in Pancreatic Cancer</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Rajeshkumar, N V ; Tan, Aik Choon ; De Oliveira, Elizabeth ; Womack, Chris ; Wombwell, Helen ; Morgan, Shethah ; Warren, Madhuri V ; Walker, Jill ; Green, Tim P ; Jimeno, Antonio ; Messersmith, Wells A ; Hidalgo, Manuel</creator><creatorcontrib>Rajeshkumar, N V ; Tan, Aik Choon ; De Oliveira, Elizabeth ; Womack, Chris ; Wombwell, Helen ; Morgan, Shethah ; Warren, Madhuri V ; Walker, Jill ; Green, Tim P ; Jimeno, Antonio ; Messersmith, Wells A ; Hidalgo, Manuel</creatorcontrib><description>Purpose: To determine the efficacy of AZD0530, an orally active small molecule Src inhibitor, in human pancreatic cancer xenografts
and to seek biomarkers predictive of activity.
Experimental Design: Sixteen patient-derived pancreatic cancer xenografts from the PancXenoBank collection at Johns Hopkins were treated with
AZD0530 (50 mg/kg/day, p.o.) for 28 days. Baseline gene expression profiles of differently expressed genes in 16 tumors by
Affymetrix U133 Plus 2.0 gene array were used to predict AZD0530 sensitivity in an independent group of eight tumors using
the K-Top Scoring Pairs ( K-TSP ) method.
Results: Three patient tumors of 16 were found to be sensitive to AZD0530, defined as tumor growth <50% compared with control tumors
(100%). Western blot and/or immunohistochemistry results showed that AZD0530 administration resulted in the down-regulation
of Src, FAK, p-FAK, p-paxillin, p-STAT-3, and XIAP in sensitive tumor xenografts compared with control tumors. The K-TSP classifier identified one gene pair ( LRRC19 and IGFBP2 ) from the 16 training cases based on a decision rule. The classifier achieved 100% and 83.3% of sensitivity and specificity
in an independent test set that consists of eight xenograft cases.
Conclusions: AZD0530 treatment significantly inhibits the tumor growth in a subset of human pancreatic tumor xenografts. One gene pair
( LRRC19 and IGFBP2 ) identified by the K-TSP classifier has high predictive power for AZD0530 sensitivity, suggesting the potential for this gene pair as biomarker for
pancreatic tumor sensitivity to AZD0530.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-08-3021</identifier><identifier>PMID: 19509160</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; AZD0530 ; Benzodioxoles - pharmacology ; Biomarkers, Tumor - metabolism ; Female ; Focal Adhesion Kinase 1 - antagonists & inhibitors ; Focal Adhesion Kinase 1 - metabolism ; Gene Expression Profiling ; Humans ; Mice ; Mice, Nude ; Pancreatic cancer ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Paxillin - antagonists & inhibitors ; Paxillin - metabolism ; Proto-Oncogene Proteins pp60(c-src) - antagonists & inhibitors ; Quinazolines - pharmacology ; Small molecule inhibitor ; Src inhibitor ; STAT3 Transcription Factor - antagonists & inhibitors ; STAT3 Transcription Factor - metabolism ; Xenograft Model Antitumor Assays</subject><ispartof>Clinical cancer research, 2009-06, Vol.15 (12), p.4138-4146</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c388t-36673f1ee74a370a7fe053882f9a3c4b9e1e10f3feffcd52341af2f8c9561aa93</citedby><cites>FETCH-LOGICAL-c388t-36673f1ee74a370a7fe053882f9a3c4b9e1e10f3feffcd52341af2f8c9561aa93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19509160$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rajeshkumar, N V</creatorcontrib><creatorcontrib>Tan, Aik Choon</creatorcontrib><creatorcontrib>De Oliveira, Elizabeth</creatorcontrib><creatorcontrib>Womack, Chris</creatorcontrib><creatorcontrib>Wombwell, Helen</creatorcontrib><creatorcontrib>Morgan, Shethah</creatorcontrib><creatorcontrib>Warren, Madhuri V</creatorcontrib><creatorcontrib>Walker, Jill</creatorcontrib><creatorcontrib>Green, Tim P</creatorcontrib><creatorcontrib>Jimeno, Antonio</creatorcontrib><creatorcontrib>Messersmith, Wells A</creatorcontrib><creatorcontrib>Hidalgo, Manuel</creatorcontrib><title>Antitumor Effects and Biomarkers of Activity of AZD0530, a Src Inhibitor, in Pancreatic Cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Purpose: To determine the efficacy of AZD0530, an orally active small molecule Src inhibitor, in human pancreatic cancer xenografts
and to seek biomarkers predictive of activity.
Experimental Design: Sixteen patient-derived pancreatic cancer xenografts from the PancXenoBank collection at Johns Hopkins were treated with
AZD0530 (50 mg/kg/day, p.o.) for 28 days. Baseline gene expression profiles of differently expressed genes in 16 tumors by
Affymetrix U133 Plus 2.0 gene array were used to predict AZD0530 sensitivity in an independent group of eight tumors using
the K-Top Scoring Pairs ( K-TSP ) method.
Results: Three patient tumors of 16 were found to be sensitive to AZD0530, defined as tumor growth <50% compared with control tumors
(100%). Western blot and/or immunohistochemistry results showed that AZD0530 administration resulted in the down-regulation
of Src, FAK, p-FAK, p-paxillin, p-STAT-3, and XIAP in sensitive tumor xenografts compared with control tumors. The K-TSP classifier identified one gene pair ( LRRC19 and IGFBP2 ) from the 16 training cases based on a decision rule. The classifier achieved 100% and 83.3% of sensitivity and specificity
in an independent test set that consists of eight xenograft cases.
Conclusions: AZD0530 treatment significantly inhibits the tumor growth in a subset of human pancreatic tumor xenografts. One gene pair
( LRRC19 and IGFBP2 ) identified by the K-TSP classifier has high predictive power for AZD0530 sensitivity, suggesting the potential for this gene pair as biomarker for
pancreatic tumor sensitivity to AZD0530.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>AZD0530</subject><subject>Benzodioxoles - pharmacology</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Female</subject><subject>Focal Adhesion Kinase 1 - antagonists & inhibitors</subject><subject>Focal Adhesion Kinase 1 - metabolism</subject><subject>Gene Expression Profiling</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Paxillin - antagonists & inhibitors</subject><subject>Paxillin - metabolism</subject><subject>Proto-Oncogene Proteins pp60(c-src) - antagonists & inhibitors</subject><subject>Quinazolines - pharmacology</subject><subject>Small molecule inhibitor</subject><subject>Src inhibitor</subject><subject>STAT3 Transcription Factor - antagonists & inhibitors</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkMlOwzAQhi0EYik8AsgnJCQCnjhOnGMJq4QEYrlwwHLdMTW0CdguqG-PuyBO8x_-RfMRsg_sBEDIU2CVzFjB85OmeciYzDjLYY1sgxBVxvNSrCf959kiOyG8MwYFsGKTbEEtWA0l2yav_Ta6OJ10nl5YiyYGqtshPXPdRPsP9IF2lvZNdN8uzhb65ZwJzo6ppo_e0Jt25AYudv6Yupbe69Z41NEZ2iSJfpdsWD0OuLe6PfJ8efHUXGe3d1c3Tf82M1zKmPGyrLgFxKrQvGK6sphGpMxtrbkpBjUCArPcorVmKHJegLa5laYWJWhd8x45XPZ--u5riiGqiQsGx2PdYjcNKtVXskjBHhFLo_FdCB6t-vQuvTpTwNQcrJpDU3NoKoFVTKo52JQ7WA1MBxMc_qdWJJPhaGkYubfRj_OozIKAx4Dam5ECoSBXBXDJfwEjSoDQ</recordid><startdate>20090615</startdate><enddate>20090615</enddate><creator>Rajeshkumar, N V</creator><creator>Tan, Aik Choon</creator><creator>De Oliveira, Elizabeth</creator><creator>Womack, Chris</creator><creator>Wombwell, Helen</creator><creator>Morgan, Shethah</creator><creator>Warren, Madhuri V</creator><creator>Walker, Jill</creator><creator>Green, Tim P</creator><creator>Jimeno, Antonio</creator><creator>Messersmith, Wells A</creator><creator>Hidalgo, Manuel</creator><general>American Association for Cancer Research</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20090615</creationdate><title>Antitumor Effects and Biomarkers of Activity of AZD0530, a Src Inhibitor, in Pancreatic Cancer</title><author>Rajeshkumar, N V ; Tan, Aik Choon ; De Oliveira, Elizabeth ; Womack, Chris ; Wombwell, Helen ; Morgan, Shethah ; Warren, Madhuri V ; Walker, Jill ; Green, Tim P ; Jimeno, Antonio ; Messersmith, Wells A ; Hidalgo, Manuel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c388t-36673f1ee74a370a7fe053882f9a3c4b9e1e10f3feffcd52341af2f8c9561aa93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>AZD0530</topic><topic>Benzodioxoles - pharmacology</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Female</topic><topic>Focal Adhesion Kinase 1 - antagonists & inhibitors</topic><topic>Focal Adhesion Kinase 1 - metabolism</topic><topic>Gene Expression Profiling</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Paxillin - antagonists & inhibitors</topic><topic>Paxillin - metabolism</topic><topic>Proto-Oncogene Proteins pp60(c-src) - antagonists & inhibitors</topic><topic>Quinazolines - pharmacology</topic><topic>Small molecule inhibitor</topic><topic>Src inhibitor</topic><topic>STAT3 Transcription Factor - antagonists & inhibitors</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rajeshkumar, N V</creatorcontrib><creatorcontrib>Tan, Aik Choon</creatorcontrib><creatorcontrib>De Oliveira, Elizabeth</creatorcontrib><creatorcontrib>Womack, Chris</creatorcontrib><creatorcontrib>Wombwell, Helen</creatorcontrib><creatorcontrib>Morgan, Shethah</creatorcontrib><creatorcontrib>Warren, Madhuri V</creatorcontrib><creatorcontrib>Walker, Jill</creatorcontrib><creatorcontrib>Green, Tim P</creatorcontrib><creatorcontrib>Jimeno, Antonio</creatorcontrib><creatorcontrib>Messersmith, Wells A</creatorcontrib><creatorcontrib>Hidalgo, Manuel</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rajeshkumar, N V</au><au>Tan, Aik Choon</au><au>De Oliveira, Elizabeth</au><au>Womack, Chris</au><au>Wombwell, Helen</au><au>Morgan, Shethah</au><au>Warren, Madhuri V</au><au>Walker, Jill</au><au>Green, Tim P</au><au>Jimeno, Antonio</au><au>Messersmith, Wells A</au><au>Hidalgo, Manuel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antitumor Effects and Biomarkers of Activity of AZD0530, a Src Inhibitor, in Pancreatic Cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2009-06-15</date><risdate>2009</risdate><volume>15</volume><issue>12</issue><spage>4138</spage><epage>4146</epage><pages>4138-4146</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Purpose: To determine the efficacy of AZD0530, an orally active small molecule Src inhibitor, in human pancreatic cancer xenografts
and to seek biomarkers predictive of activity.
Experimental Design: Sixteen patient-derived pancreatic cancer xenografts from the PancXenoBank collection at Johns Hopkins were treated with
AZD0530 (50 mg/kg/day, p.o.) for 28 days. Baseline gene expression profiles of differently expressed genes in 16 tumors by
Affymetrix U133 Plus 2.0 gene array were used to predict AZD0530 sensitivity in an independent group of eight tumors using
the K-Top Scoring Pairs ( K-TSP ) method.
Results: Three patient tumors of 16 were found to be sensitive to AZD0530, defined as tumor growth <50% compared with control tumors
(100%). Western blot and/or immunohistochemistry results showed that AZD0530 administration resulted in the down-regulation
of Src, FAK, p-FAK, p-paxillin, p-STAT-3, and XIAP in sensitive tumor xenografts compared with control tumors. The K-TSP classifier identified one gene pair ( LRRC19 and IGFBP2 ) from the 16 training cases based on a decision rule. The classifier achieved 100% and 83.3% of sensitivity and specificity
in an independent test set that consists of eight xenograft cases.
Conclusions: AZD0530 treatment significantly inhibits the tumor growth in a subset of human pancreatic tumor xenografts. One gene pair
( LRRC19 and IGFBP2 ) identified by the K-TSP classifier has high predictive power for AZD0530 sensitivity, suggesting the potential for this gene pair as biomarker for
pancreatic tumor sensitivity to AZD0530.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>19509160</pmid><doi>10.1158/1078-0432.CCR-08-3021</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-0432 |
| ispartof | Clinical cancer research, 2009-06, Vol.15 (12), p.4138-4146 |
| issn | 1078-0432 1557-3265 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_67378452 |
| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Antineoplastic Agents - pharmacology AZD0530 Benzodioxoles - pharmacology Biomarkers, Tumor - metabolism Female Focal Adhesion Kinase 1 - antagonists & inhibitors Focal Adhesion Kinase 1 - metabolism Gene Expression Profiling Humans Mice Mice, Nude Pancreatic cancer Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Paxillin - antagonists & inhibitors Paxillin - metabolism Proto-Oncogene Proteins pp60(c-src) - antagonists & inhibitors Quinazolines - pharmacology Small molecule inhibitor Src inhibitor STAT3 Transcription Factor - antagonists & inhibitors STAT3 Transcription Factor - metabolism Xenograft Model Antitumor Assays |
| title | Antitumor Effects and Biomarkers of Activity of AZD0530, a Src Inhibitor, in Pancreatic Cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T20%3A45%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Antitumor%20Effects%20and%20Biomarkers%20of%20Activity%20of%20AZD0530,%20a%20Src%20Inhibitor,%20in%20Pancreatic%20Cancer&rft.jtitle=Clinical%20cancer%20research&rft.au=Rajeshkumar,%20N%20V&rft.date=2009-06-15&rft.volume=15&rft.issue=12&rft.spage=4138&rft.epage=4146&rft.pages=4138-4146&rft.issn=1078-0432&rft.eissn=1557-3265&rft_id=info:doi/10.1158/1078-0432.CCR-08-3021&rft_dat=%3Cproquest_cross%3E67378452%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=67378452&rft_id=info:pmid/19509160&rfr_iscdi=true |