Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer

Persistent Link:
http://hdl.handle.net/10150/618060
Title:
Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer
Author:
Witkiewicz, Agnieszka K.; Balaji, Uthra; Eslinger, Cody; McMillan, Elizabeth; Conway, William; Posner, Bruce; Mills, Gordon B.; O’Reilly, Eileen M.; Knudsen, Erik S.
Affiliation:
Department of Pathology, University of Arizona; University of Arizona Cancer Center, University of Arizona; Department of Medicine, University of Arizona
Issue Date:
2016-08
Publisher:
Cell Press
Citation:
Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer 2016 Cell Reports
Journal:
Cell Reports
Rights:
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Collection Information:
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) harbors the worst prognosis of any common solid tumor, and multiple failed clinical trials indicate therapeutic recalcitrance. Here, we use exome sequencing of patient tumors and find multiple conserved genetic alterations. However, the majority of tumors exhibit no clearly defined therapeutic target. High-throughput drug screens using patient-derived cell lines found rare examples of sensitivity to monotherapy, with most models requiring combination therapy. Using PDX models, we confirmed the effectiveness and selectivity of the identified treatment responses. Out of more than 500 single and combination drug regimens tested, no single treatment was effective for the majority of PDAC tumors, and each case had unique sensitivity profiles that could not be predicted using genetic analyses. These data indicate a shortcoming of reliance on genetic analysis to predict efficacy of currently available agents against PDAC and suggest that sensitivity profiling of patient-derived models could inform personalized therapy design for PDAC.
ISSN:
22111247
DOI:
10.1016/j.celrep.2016.07.023
Version:
Final published version
Sponsors:
The authors thank members of the E.S.K. and A.K.W. laboratories for thoughtprovoking discussion, technical assistance, and help with manuscript preparation. Nicholas Borja and Eboni Holloman assisted with select animal studies. Ngoc Haoi assisted with informatics and figure development. The Tissue Management Shared Resource of the Simmons Cancer Center (Cheryl Lewis, manager) assisted with the acquisition of the tissue and coordinating histological and immunohistochemical analysis of tumor specimens. The High-Throughput Screening core and Tissue Management Shared Resource are supported by the Cancer Center Support grant of the Simmons Cancer Center (P30 CA142543). The research is supported by grants to A.K.W. and E.S.K. from the NIH (CA142543-05S2).
Additional Links:
http://linkinghub.elsevier.com/retrieve/pii/S221112471630924X

Full metadata record

DC FieldValue Language
dc.contributor.authorWitkiewicz, Agnieszka K.en
dc.contributor.authorBalaji, Uthraen
dc.contributor.authorEslinger, Codyen
dc.contributor.authorMcMillan, Elizabethen
dc.contributor.authorConway, Williamen
dc.contributor.authorPosner, Bruceen
dc.contributor.authorMills, Gordon B.en
dc.contributor.authorO’Reilly, Eileen M.en
dc.contributor.authorKnudsen, Erik S.en
dc.date.accessioned2016-08-08T22:58:00Z-
dc.date.available2016-08-08T22:58:00Z-
dc.date.issued2016-08-
dc.identifier.citationIntegrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer 2016 Cell Reportsen
dc.identifier.issn22111247-
dc.identifier.doi10.1016/j.celrep.2016.07.023-
dc.identifier.urihttp://hdl.handle.net/10150/618060-
dc.description.abstractPancreatic ductal adenocarcinoma (PDAC) harbors the worst prognosis of any common solid tumor, and multiple failed clinical trials indicate therapeutic recalcitrance. Here, we use exome sequencing of patient tumors and find multiple conserved genetic alterations. However, the majority of tumors exhibit no clearly defined therapeutic target. High-throughput drug screens using patient-derived cell lines found rare examples of sensitivity to monotherapy, with most models requiring combination therapy. Using PDX models, we confirmed the effectiveness and selectivity of the identified treatment responses. Out of more than 500 single and combination drug regimens tested, no single treatment was effective for the majority of PDAC tumors, and each case had unique sensitivity profiles that could not be predicted using genetic analyses. These data indicate a shortcoming of reliance on genetic analysis to predict efficacy of currently available agents against PDAC and suggest that sensitivity profiling of patient-derived models could inform personalized therapy design for PDAC.en
dc.description.sponsorshipThe authors thank members of the E.S.K. and A.K.W. laboratories for thoughtprovoking discussion, technical assistance, and help with manuscript preparation. Nicholas Borja and Eboni Holloman assisted with select animal studies. Ngoc Haoi assisted with informatics and figure development. The Tissue Management Shared Resource of the Simmons Cancer Center (Cheryl Lewis, manager) assisted with the acquisition of the tissue and coordinating histological and immunohistochemical analysis of tumor specimens. The High-Throughput Screening core and Tissue Management Shared Resource are supported by the Cancer Center Support grant of the Simmons Cancer Center (P30 CA142543). The research is supported by grants to A.K.W. and E.S.K. from the NIH (CA142543-05S2).en
dc.language.isoenen
dc.publisherCell Pressen
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S221112471630924Xen
dc.rightsThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).en
dc.titleIntegrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Canceren
dc.typeArticleen
dc.contributor.departmentDepartment of Pathology, University of Arizonaen
dc.contributor.departmentUniversity of Arizona Cancer Center, University of Arizonaen
dc.contributor.departmentDepartment of Medicine, University of Arizonaen
dc.identifier.journalCell Reportsen
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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