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

Agnieszka K. Witkiewicz, Uthra Balaji, Cody Eslinger, Elizabeth McMillan, William Conway, Bruce Posner, Gordon B. Mills, Eileen M. O'Reilly, Erik S. Knudsen

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2017-2031
Number of pages15
JournalCell Reports
Volume16
Issue number7
DOIs
StatePublished - Aug 16 2016

Fingerprint

Pancreatic Neoplasms
Tumors
Adenocarcinoma
Neoplasms
Drug Combinations
Therapeutics
Ports and harbors
Exome
Cells
Throughput
Clinical Trials
Pharmaceutical Preparations
Cell Line

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer. / Witkiewicz, Agnieszka K.; Balaji, Uthra; Eslinger, Cody; McMillan, Elizabeth; Conway, William; Posner, Bruce; Mills, Gordon B.; O'Reilly, Eileen M.; Knudsen, Erik S.

In: Cell Reports, Vol. 16, No. 7, 16.08.2016, p. 2017-2031.

Research output: Contribution to journalArticle

Witkiewicz, AK, Balaji, U, Eslinger, C, McMillan, E, Conway, W, Posner, B, Mills, GB, O'Reilly, EM & Knudsen, ES 2016, 'Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer', Cell Reports, vol. 16, no. 7, pp. 2017-2031. https://doi.org/10.1016/j.celrep.2016.07.023
Witkiewicz, Agnieszka K. ; Balaji, Uthra ; Eslinger, Cody ; McMillan, Elizabeth ; Conway, William ; Posner, Bruce ; Mills, Gordon B. ; O'Reilly, Eileen M. ; Knudsen, Erik S. / Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer. In: Cell Reports. 2016 ; Vol. 16, No. 7. pp. 2017-2031.
@article{a1447c52ddc04539b4173c9be9719a4d,
title = "Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer",
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.",
author = "Witkiewicz, {Agnieszka K.} and Uthra Balaji and Cody Eslinger and Elizabeth McMillan and William Conway and Bruce Posner and Mills, {Gordon B.} and O'Reilly, {Eileen M.} and Knudsen, {Erik S.}",
year = "2016",
month = "8",
day = "16",
doi = "10.1016/j.celrep.2016.07.023",
language = "English (US)",
volume = "16",
pages = "2017--2031",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",

}

TY - JOUR

T1 - Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer

AU - Witkiewicz, Agnieszka K.

AU - Balaji, Uthra

AU - Eslinger, Cody

AU - McMillan, Elizabeth

AU - Conway, William

AU - Posner, Bruce

AU - Mills, Gordon B.

AU - O'Reilly, Eileen M.

AU - Knudsen, Erik S.

PY - 2016/8/16

Y1 - 2016/8/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84997637203&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84997637203&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2016.07.023

DO - 10.1016/j.celrep.2016.07.023

M3 - Article

VL - 16

SP - 2017

EP - 2031

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 7

ER -