Organoid profiling identifies common responders to chemotherapy in pancreatic cancer

Hervé Tiriac; Pascal Belleau; Dannielle D. Engle; Dennis Plenker; Astrid Deschênes; Tim D.D. Somerville; Fieke E.M. Froeling; Richard A. Burkhart; Robert E. Denroche; Gun Ho Jang; Koji Miyabayashi; C. Megan Young; Hardik Patel; Michelle Ma; Joseph F. Lacomb; Randze Lerie D. Palmaira; Ammar A. Javed; Jasmine C. Huynh; Molly Johnson; Kanika Arora; Nicolas Robine; Minita Shah; Rashesh Sanghvi; Austin B. Goetz; Cinthya Y. Lowder; Laura Martello; Else Driehuis; Nicolas Lecomte; Gokce Askan; Christine A. Iacobuzio-Donahue; Hans Clevers; Laura D. Wood; Ralph H. Hruban; Elizabeth Thompson; Andrew J. Aguirre; Brian M. Wolpin; Aaron Sasson; Joseph Kim; Maoxin Wu; Juan Carlos Bucobo; Peter Allen; Divyesh V. Sejpal; William Nealon; James D. Sullivan; Jordan M. Winter; Phyllis A. Gimotty; Jean L. Grem; Dominick J. Dimaio; Jonathan M. Buscaglia; Paul M. Grandgenett; Jonathan R. Brody; Michael A. Hollingsworth; Grainne M. O’kane; Faiyaz Notta; Edward Kim; James M. Crawford; Craig Devoe; Allyson Ocean; Christopher L. Wolfgang; Kenneth H. Yu; Ellen Li; Christopher R. Vakoc; Benjamin Hubert; Sandra E. Fischer; Julie M. Wilson; Richard Moffitt; Jennifer Knox; Alexander Krasnitz; Steven Gallinger; David A. Tuveson

doi:10.1158/2159-8290.CD-18-0349

Organoid profiling identifies common responders to chemotherapy in pancreatic cancer

Hervé Tiriac, Pascal Belleau, Dannielle D. Engle, Dennis Plenker, Astrid Deschênes, Tim D.D. Somerville, Fieke E.M. Froeling, Richard A. Burkhart, Robert E. Denroche, Gun Ho Jang, Koji Miyabayashi, C. Megan Young, Hardik Patel, Michelle Ma, Joseph F. Lacomb, Randze Lerie D. Palmaira, Ammar A. Javed, Jasmine C. Huynh, Molly Johnson, Kanika AroraNicolas Robine, Minita Shah, Rashesh Sanghvi, Austin B. Goetz, Cinthya Y. Lowder, Laura Martello, Else Driehuis, Nicolas Lecomte, Gokce Askan, Christine A. Iacobuzio-Donahue, Hans Clevers, Laura D. Wood, Ralph H. Hruban, Elizabeth Thompson, Andrew J. Aguirre, Brian M. Wolpin, Aaron Sasson, Joseph Kim, Maoxin Wu, Juan Carlos Bucobo, Peter Allen, Divyesh V. Sejpal, William Nealon, James D. Sullivan, Jordan M. Winter, Phyllis A. Gimotty, Jean L. Grem, Dominick J. Dimaio, Jonathan M. Buscaglia, Paul M. Grandgenett, Jonathan R. Brody, Michael A. Hollingsworth, Grainne M. O’kane, Faiyaz Notta, Edward Kim, James M. Crawford, Craig Devoe, Allyson Ocean, Christopher L. Wolfgang, Kenneth H. Yu, Ellen Li, Christopher R. Vakoc, Benjamin Hubert, Sandra E. Fischer, Julie M. Wilson, Richard Moffitt, Jennifer Knox, Alexander Krasnitz, Steven Gallinger, David A. Tuveson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

14 Citations (Scopus)

Abstract

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. ©2018 AACR. See related commentary by Collisson, p. 1062 This article is highlighted in the In This Issue feature, p. 1047.

Original language	English
Pages (from-to)	1112-1129
Number of pages	18
Journal	Cancer Discovery
Volume	8
Issue number	9
DOIs	https://doi.org/10.1158/2159-8290.CD-18-0349
Publication status	Published - 1 Sept 2018

Keywords

Antineoplastic Agents/pharmacology
Drug Resistance, Neoplasm/drug effects
Drug Screening Assays, Antitumor
Gene Expression Profiling/methods
Gene Expression Regulation, Neoplastic/drug effects
Gene Regulatory Networks/drug effects
Humans
Molecular Targeted Therapy
Organoids/chemistry
Pancreatic Neoplasms/drug therapy
Precision Medicine
Prospective Studies
Sequence Analysis, RNA
Standard of Care
Tumor Cells, Cultured

Access to Document

10.1158/2159-8290.CD-18-0349

Cite this

Tiriac, H., Belleau, P., Engle, D. D., Plenker, D., Deschênes, A., Somerville, T. D. D., Froeling, F. E. M., Burkhart, R. A., Denroche, R. E., Jang, G. H., Miyabayashi, K., Young, C. M., Patel, H., Ma, M., Lacomb, J. F., Palmaira, R. L. D., Javed, A. A., Huynh, J. C., Johnson, M., ... Tuveson, D. A. (2018). Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. Cancer Discovery, 8(9), 1112-1129. https://doi.org/10.1158/2159-8290.CD-18-0349

@article{1626fef028524e8bb9caba2f865c064d,

title = "Organoid profiling identifies common responders to chemotherapy in pancreatic cancer",

abstract = "Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. {\textcopyright}2018 AACR. See related commentary by Collisson, p. 1062 This article is highlighted in the In This Issue feature, p. 1047. ",

keywords = "Antineoplastic Agents/pharmacology, Drug Resistance, Neoplasm/drug effects, Drug Screening Assays, Antitumor, Gene Expression Profiling/methods, Gene Expression Regulation, Neoplastic/drug effects, Gene Regulatory Networks/drug effects, Humans, Molecular Targeted Therapy, Organoids/chemistry, Pancreatic Neoplasms/drug therapy, Precision Medicine, Prospective Studies, Sequence Analysis, RNA, Standard of Care, Tumor Cells, Cultured",

author = "Herv{\'e} Tiriac and Pascal Belleau and Engle, {Dannielle D.} and Dennis Plenker and Astrid Desch{\^e}nes and Somerville, {Tim D.D.} and Froeling, {Fieke E.M.} and Burkhart, {Richard A.} and Denroche, {Robert E.} and Jang, {Gun Ho} and Koji Miyabayashi and Young, {C. Megan} and Hardik Patel and Michelle Ma and Lacomb, {Joseph F.} and Palmaira, {Randze Lerie D.} and Javed, {Ammar A.} and Huynh, {Jasmine C.} and Molly Johnson and Kanika Arora and Nicolas Robine and Minita Shah and Rashesh Sanghvi and Goetz, {Austin B.} and Lowder, {Cinthya Y.} and Laura Martello and Else Driehuis and Nicolas Lecomte and Gokce Askan and Iacobuzio-Donahue, {Christine A.} and Hans Clevers and Wood, {Laura D.} and Hruban, {Ralph H.} and Elizabeth Thompson and Aguirre, {Andrew J.} and Wolpin, {Brian M.} and Aaron Sasson and Joseph Kim and Maoxin Wu and Bucobo, {Juan Carlos} and Peter Allen and Sejpal, {Divyesh V.} and William Nealon and Sullivan, {James D.} and Winter, {Jordan M.} and Gimotty, {Phyllis A.} and Grem, {Jean L.} and Dimaio, {Dominick J.} and Buscaglia, {Jonathan M.} and Grandgenett, {Paul M.} and Brody, {Jonathan R.} and Hollingsworth, {Michael A.} and O{\textquoteright}kane, {Grainne M.} and Faiyaz Notta and Edward Kim and Crawford, {James M.} and Craig Devoe and Allyson Ocean and Wolfgang, {Christopher L.} and Yu, {Kenneth H.} and Ellen Li and Vakoc, {Christopher R.} and Benjamin Hubert and Fischer, {Sandra E.} and Wilson, {Julie M.} and Richard Moffitt and Jennifer Knox and Alexander Krasnitz and Steven Gallinger and Tuveson, {David A.}",

note = "Funding Information: We would like to thank the patients, families, and clinicians who contributed to this work. This work was supported by the Lustgarten Foundation (D.A. Tuveson). D.A. Tuveson is a distinguished scholar of the Lustgarten Foundation and Director of the Lustgarten Foundation Dedicated Laboratory of Pancreatic Cancer Research. S. Gallinger is supported by the Ontario Institute for Cancer Research, charitable donations from the Canadian Friends of the Hebrew University (Alex U. Soyka) and the Pancreatic Cancer Canada Foundation, and the Leb-ovich Chair in Hepatobiliary/Pancreatic Surgical Oncology. This project was also supported in part by the NCI/LEIDOS Human Cancer Models Initiative (HHSN26100008; D.A. Tuveson, H. Clevers, and J.M. Crawford), NIH 5P50CA101955-07 (D.A. Tuveson), P20CA192996-03 (D.A. Tuveson), 1U10CA180944-04 (D.A. Tuveson), 5U01CA168409-5 (D.A. Tuveson), 1R01CA188134-01 (D.A. Tuveson), 1R01CA190092-04 (D.A. Tuveson), 5T32CA148056 (D.D. Engle), 5K99CA204725 (D.D. Engle), 5P01CA013106 (C.R. Vakoc), 5P30CA45508 (D.A. Tuve-son and P.A. Gilmoty), 1R01CA212600-01 (J.R. Brody and J.M. Winter), P20CA192994 (E. Li), R01CA202762 (K.H. Yu), P50CA127297 (M.A. Hollingsworth; UNMC RAP), U01CA210240 (M.A. Hollings-worth, D.A. Tuveson; UNMC RAP), and 5R50CA211462 (M.A. Hol-lingsworth; UNMC RAP), V Foundation Translational Grant (K.H. Yu and D.A. Tuveson), Cold Spring Harbor Laboratory Association (D.A. Tuveson), Stand Up To Cancer/AACRPS09 (D.A. Tuveson), Precision Medicine Research Associates (D.A. Tuveson), SWOG ITSC 5U10CA180944-04 (D.A. Tuveson, H. Tiriac, and E.J. Kim), Pancreatic Cancer Action Network-AACR 16-20-25-VAKO (C.R.Vakoc), State of New York C150158 (T.D.D. Somerville; the opinions, results, findings, and/or interpretation of data contained herein are the responsibility of the authors and do not necessarily represent the opinions, interpretations or policy of New York State), Concetta Greenberg in memory of Marvin S. Greenberg, MD (J.R. Brody and J.M. Winter), RAN grant from the AACR Pancreatic Cancer Action Network (J.R. Brody and J.M. Winter), ASGE Endoscopic Research Award 71040 (J.M. Buscaglia), Simons Foundation Award 415604 (E. Li), and Canadian Cancer Society Research Institute grant 702316 (S. Gall-inger). We acknowledge the Cold Spring Harbor Laboratory Tissue Culture and Next Generation Sequencing Shared Resources, which are funded by NIH Cancer Center Support Grant 5P30CA045508. We also acknowledge the contributions of Production Sequencing, Genome Sequencing Informatics and Tissue Portal (Diagnostic Development) at the Ontario Institute for Cancer Research, as well as the University Health Network BioBank. The pancreatic cancer patient study (ICGC-CA, COMPASS) was conducted with the support of the Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario. Funding Information: We would like to thank the patients, families, and clinicians who contributed to this work. This work was supported by the Lustgarten Foundation (D.A. Tuveson). D.A. Tuveson is a distinguished scholar of the Lustgarten Foundation and Director of the Lustgarten Foundation Dedicated Laboratory of Pancreatic Cancer Research. S. Gallinger is supported by the Ontario Institute for Cancer Research, charitable donations from the Canadian Friends of the Hebrew University (Alex U. Soyka) and the Pancreatic Cancer Canada Foundation, and the Lebovich Chair in Hepatobiliary/Pancreatic Surgical Oncology. This project was also supported in part by the NCI/LEIDOS Human Cancer Models Initiative (HHSN26100008; D.A. Tuveson, H. Clevers, and J.M. Crawford), NIH5P50CA101955-07 (D.A. Tuveson), P20CA192996-03 (D.A. Tuveson), 1U10CA180944-04 (D.A. Tuveson), 5U01CA168409-5 (D.A. Tuveson), 1R01CA188134-01 (D.A. Tuveson), 1R01CA190092-04 (D.A. Tuveson), 5T32CA148056 (D.D. Engle), 5K99CA204725 (D.D. Engle), 5P01CA013106 (C.R. Vakoc), 5P30CA45508 (D.A. Tuveson and P.A. Gilmoty), 1R01CA212600-01 (J.R. Brody and J.M. Winter), P20CA192994 (E. Li), R01CA202762 (K.H. Yu), P50CA127297 (M.A. Hollingsworth; UNMC RAP), U01CA210240 (M.A. Hollingsworth, D.A. Tuveson; UNMC RAP), and 5R50CA211462 (M.A. Hollingsworth; UNMC RAP), V Foundation Translational Grant (K.H. Yu and D.A. Tuveson), Cold Spring Harbor Laboratory Association (D.A. Tuveson), Stand Up To Cancer/AACRPS09 (D.A. Tuveson), Precision Medicine Research Associates (D.A. Tuveson), SWOG ITSC 5U10CA180944-04 (D.A. Tuveson, H. Tiriac, and E.J. Kim), Pancreatic Cancer Action Network-AACR 16-20-25-VAKO (C.R.Vakoc), State of New York C150158 (T.D.D. Somerville; the opinions, results, findings, and/or interpretation of data contained herein are the responsibility of the authors and do not necessarily represent the opinions, interpretations or policy of New York State), Concetta Greenberg in memory of Marvin S. Greenberg, MD (J.R. Brody and J.M. Winter), RAN grant from the AACRPancreatic Cancer Action Network (J.R. Brody and J.M. Winter), ASGE Endoscopic Research Award 71040 (J.M. Buscaglia), Simons Foundation Award 415604 (E. Li), and Canadian Cancer Society Research Institute grant 702316 (S. Gallinger). We acknowledge the Cold Spring Harbor Laboratory Tissue Culture and Next Generation Sequencing Shared Resources, which are funded by NIH Cancer Center Support Grant 5P30CA045508. We also acknowledge the contributions of Production Sequencing, Genome Sequencing Informatics and Tissue Portal (Diagnostic Development) at the Ontario Institute for Cancer Research, as well as the University Health Network BioBank. The pancreatic cancer patient study (ICGC-CA, COMPASS) was conducted with the support of the Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario. Funding Information: L.D. Wood is a consultant/advisory board member for Personal Genome Diagnostics. R.H. Hruban is a board member for MyDiag-nostics and reports receiving royalties from UpToDate. B.M. Wolpin reports receiving a commercial research grant from Celgene. A. Sasson has ownership interest (including patents) in Sanguine Diagnostics and Therapeutics. C.R. Vakoc reports receiving a commercial research grant from Boehringer Ingelheim and is a consultant/advisory board member for KSQ Therapeutics. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright}2018 American Association for Cancer Research.",

year = "2018",

month = sep,

day = "1",

doi = "10.1158/2159-8290.CD-18-0349",

language = "English",

volume = "8",

pages = "1112--1129",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "9",

}

Tiriac, H, Belleau, P, Engle, DD, Plenker, D, Deschênes, A, Somerville, TDD, Froeling, FEM, Burkhart, RA, Denroche, RE, Jang, GH, Miyabayashi, K, Young, CM, Patel, H, Ma, M, Lacomb, JF, Palmaira, RLD, Javed, AA, Huynh, JC, Johnson, M, Arora, K, Robine, N, Shah, M, Sanghvi, R, Goetz, AB, Lowder, CY, Martello, L, Driehuis, E, Lecomte, N, Askan, G, Iacobuzio-Donahue, CA, Clevers, H, Wood, LD, Hruban, RH, Thompson, E, Aguirre, AJ, Wolpin, BM, Sasson, A, Kim, J, Wu, M, Bucobo, JC, Allen, P, Sejpal, DV, Nealon, W, Sullivan, JD, Winter, JM, Gimotty, PA, Grem, JL, Dimaio, DJ, Buscaglia, JM, Grandgenett, PM, Brody, JR, Hollingsworth, MA, O’kane, GM, Notta, F, Kim, E, Crawford, JM, Devoe, C, Ocean, A, Wolfgang, CL, Yu, KH, Li, E, Vakoc, CR, Hubert, B, Fischer, SE, Wilson, JM, Moffitt, R, Knox, J, Krasnitz, A, Gallinger, S & Tuveson, DA 2018, 'Organoid profiling identifies common responders to chemotherapy in pancreatic cancer', Cancer Discovery, vol. 8, no. 9, pp. 1112-1129. https://doi.org/10.1158/2159-8290.CD-18-0349

TY - JOUR

T1 - Organoid profiling identifies common responders to chemotherapy in pancreatic cancer

AU - Tiriac, Hervé

AU - Belleau, Pascal

AU - Engle, Dannielle D.

AU - Plenker, Dennis

AU - Deschênes, Astrid

AU - Somerville, Tim D.D.

AU - Froeling, Fieke E.M.

AU - Burkhart, Richard A.

AU - Denroche, Robert E.

AU - Jang, Gun Ho

AU - Miyabayashi, Koji

AU - Young, C. Megan

AU - Patel, Hardik

AU - Ma, Michelle

AU - Lacomb, Joseph F.

AU - Palmaira, Randze Lerie D.

AU - Javed, Ammar A.

AU - Huynh, Jasmine C.

AU - Johnson, Molly

AU - Arora, Kanika

AU - Robine, Nicolas

AU - Shah, Minita

AU - Sanghvi, Rashesh

AU - Goetz, Austin B.

AU - Lowder, Cinthya Y.

AU - Martello, Laura

AU - Driehuis, Else

AU - Lecomte, Nicolas

AU - Askan, Gokce

AU - Iacobuzio-Donahue, Christine A.

AU - Clevers, Hans

AU - Wood, Laura D.

AU - Hruban, Ralph H.

AU - Thompson, Elizabeth

AU - Aguirre, Andrew J.

AU - Wolpin, Brian M.

AU - Sasson, Aaron

AU - Kim, Joseph

AU - Wu, Maoxin

AU - Bucobo, Juan Carlos

AU - Allen, Peter

AU - Sejpal, Divyesh V.

AU - Nealon, William

AU - Sullivan, James D.

AU - Winter, Jordan M.

AU - Gimotty, Phyllis A.

AU - Grem, Jean L.

AU - Dimaio, Dominick J.

AU - Buscaglia, Jonathan M.

AU - Grandgenett, Paul M.

AU - Brody, Jonathan R.

AU - Hollingsworth, Michael A.

AU - O’kane, Grainne M.

AU - Notta, Faiyaz

AU - Kim, Edward

AU - Crawford, James M.

AU - Devoe, Craig

AU - Ocean, Allyson

AU - Wolfgang, Christopher L.

AU - Yu, Kenneth H.

AU - Li, Ellen

AU - Vakoc, Christopher R.

AU - Hubert, Benjamin

AU - Fischer, Sandra E.

AU - Wilson, Julie M.

AU - Moffitt, Richard

AU - Knox, Jennifer

AU - Krasnitz, Alexander

AU - Gallinger, Steven

AU - Tuveson, David A.

N1 - Funding Information: We would like to thank the patients, families, and clinicians who contributed to this work. This work was supported by the Lustgarten Foundation (D.A. Tuveson). D.A. Tuveson is a distinguished scholar of the Lustgarten Foundation and Director of the Lustgarten Foundation Dedicated Laboratory of Pancreatic Cancer Research. S. Gallinger is supported by the Ontario Institute for Cancer Research, charitable donations from the Canadian Friends of the Hebrew University (Alex U. Soyka) and the Pancreatic Cancer Canada Foundation, and the Leb-ovich Chair in Hepatobiliary/Pancreatic Surgical Oncology. This project was also supported in part by the NCI/LEIDOS Human Cancer Models Initiative (HHSN26100008; D.A. Tuveson, H. Clevers, and J.M. Crawford), NIH 5P50CA101955-07 (D.A. Tuveson), P20CA192996-03 (D.A. Tuveson), 1U10CA180944-04 (D.A. Tuveson), 5U01CA168409-5 (D.A. Tuveson), 1R01CA188134-01 (D.A. Tuveson), 1R01CA190092-04 (D.A. Tuveson), 5T32CA148056 (D.D. Engle), 5K99CA204725 (D.D. Engle), 5P01CA013106 (C.R. Vakoc), 5P30CA45508 (D.A. Tuve-son and P.A. Gilmoty), 1R01CA212600-01 (J.R. Brody and J.M. Winter), P20CA192994 (E. Li), R01CA202762 (K.H. Yu), P50CA127297 (M.A. Hollingsworth; UNMC RAP), U01CA210240 (M.A. Hollings-worth, D.A. Tuveson; UNMC RAP), and 5R50CA211462 (M.A. Hol-lingsworth; UNMC RAP), V Foundation Translational Grant (K.H. Yu and D.A. Tuveson), Cold Spring Harbor Laboratory Association (D.A. Tuveson), Stand Up To Cancer/AACRPS09 (D.A. Tuveson), Precision Medicine Research Associates (D.A. Tuveson), SWOG ITSC 5U10CA180944-04 (D.A. Tuveson, H. Tiriac, and E.J. Kim), Pancreatic Cancer Action Network-AACR 16-20-25-VAKO (C.R.Vakoc), State of New York C150158 (T.D.D. Somerville; the opinions, results, findings, and/or interpretation of data contained herein are the responsibility of the authors and do not necessarily represent the opinions, interpretations or policy of New York State), Concetta Greenberg in memory of Marvin S. Greenberg, MD (J.R. Brody and J.M. Winter), RAN grant from the AACR Pancreatic Cancer Action Network (J.R. Brody and J.M. Winter), ASGE Endoscopic Research Award 71040 (J.M. Buscaglia), Simons Foundation Award 415604 (E. Li), and Canadian Cancer Society Research Institute grant 702316 (S. Gall-inger). We acknowledge the Cold Spring Harbor Laboratory Tissue Culture and Next Generation Sequencing Shared Resources, which are funded by NIH Cancer Center Support Grant 5P30CA045508. We also acknowledge the contributions of Production Sequencing, Genome Sequencing Informatics and Tissue Portal (Diagnostic Development) at the Ontario Institute for Cancer Research, as well as the University Health Network BioBank. The pancreatic cancer patient study (ICGC-CA, COMPASS) was conducted with the support of the Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario. Funding Information: We would like to thank the patients, families, and clinicians who contributed to this work. This work was supported by the Lustgarten Foundation (D.A. Tuveson). D.A. Tuveson is a distinguished scholar of the Lustgarten Foundation and Director of the Lustgarten Foundation Dedicated Laboratory of Pancreatic Cancer Research. S. Gallinger is supported by the Ontario Institute for Cancer Research, charitable donations from the Canadian Friends of the Hebrew University (Alex U. Soyka) and the Pancreatic Cancer Canada Foundation, and the Lebovich Chair in Hepatobiliary/Pancreatic Surgical Oncology. This project was also supported in part by the NCI/LEIDOS Human Cancer Models Initiative (HHSN26100008; D.A. Tuveson, H. Clevers, and J.M. Crawford), NIH5P50CA101955-07 (D.A. Tuveson), P20CA192996-03 (D.A. Tuveson), 1U10CA180944-04 (D.A. Tuveson), 5U01CA168409-5 (D.A. Tuveson), 1R01CA188134-01 (D.A. Tuveson), 1R01CA190092-04 (D.A. Tuveson), 5T32CA148056 (D.D. Engle), 5K99CA204725 (D.D. Engle), 5P01CA013106 (C.R. Vakoc), 5P30CA45508 (D.A. Tuveson and P.A. Gilmoty), 1R01CA212600-01 (J.R. Brody and J.M. Winter), P20CA192994 (E. Li), R01CA202762 (K.H. Yu), P50CA127297 (M.A. Hollingsworth; UNMC RAP), U01CA210240 (M.A. Hollingsworth, D.A. Tuveson; UNMC RAP), and 5R50CA211462 (M.A. Hollingsworth; UNMC RAP), V Foundation Translational Grant (K.H. Yu and D.A. Tuveson), Cold Spring Harbor Laboratory Association (D.A. Tuveson), Stand Up To Cancer/AACRPS09 (D.A. Tuveson), Precision Medicine Research Associates (D.A. Tuveson), SWOG ITSC 5U10CA180944-04 (D.A. Tuveson, H. Tiriac, and E.J. Kim), Pancreatic Cancer Action Network-AACR 16-20-25-VAKO (C.R.Vakoc), State of New York C150158 (T.D.D. Somerville; the opinions, results, findings, and/or interpretation of data contained herein are the responsibility of the authors and do not necessarily represent the opinions, interpretations or policy of New York State), Concetta Greenberg in memory of Marvin S. Greenberg, MD (J.R. Brody and J.M. Winter), RAN grant from the AACRPancreatic Cancer Action Network (J.R. Brody and J.M. Winter), ASGE Endoscopic Research Award 71040 (J.M. Buscaglia), Simons Foundation Award 415604 (E. Li), and Canadian Cancer Society Research Institute grant 702316 (S. Gallinger). We acknowledge the Cold Spring Harbor Laboratory Tissue Culture and Next Generation Sequencing Shared Resources, which are funded by NIH Cancer Center Support Grant 5P30CA045508. We also acknowledge the contributions of Production Sequencing, Genome Sequencing Informatics and Tissue Portal (Diagnostic Development) at the Ontario Institute for Cancer Research, as well as the University Health Network BioBank. The pancreatic cancer patient study (ICGC-CA, COMPASS) was conducted with the support of the Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario. Funding Information: L.D. Wood is a consultant/advisory board member for Personal Genome Diagnostics. R.H. Hruban is a board member for MyDiag-nostics and reports receiving royalties from UpToDate. B.M. Wolpin reports receiving a commercial research grant from Celgene. A. Sasson has ownership interest (including patents) in Sanguine Diagnostics and Therapeutics. C.R. Vakoc reports receiving a commercial research grant from Boehringer Ingelheim and is a consultant/advisory board member for KSQ Therapeutics. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: ©2018 American Association for Cancer Research.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. ©2018 AACR. See related commentary by Collisson, p. 1062 This article is highlighted in the In This Issue feature, p. 1047.

AB - Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. ©2018 AACR. See related commentary by Collisson, p. 1062 This article is highlighted in the In This Issue feature, p. 1047.

KW - Antineoplastic Agents/pharmacology

KW - Drug Resistance, Neoplasm/drug effects

KW - Drug Screening Assays, Antitumor

KW - Gene Expression Profiling/methods

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Gene Regulatory Networks/drug effects

KW - Humans

KW - Molecular Targeted Therapy

KW - Organoids/chemistry

KW - Pancreatic Neoplasms/drug therapy

KW - Precision Medicine

KW - Prospective Studies

KW - Sequence Analysis, RNA

KW - Standard of Care

KW - Tumor Cells, Cultured

UR - http://www.scopus.com/inward/record.url?scp=85050700556&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-18-0349

DO - 10.1158/2159-8290.CD-18-0349

M3 - Article

C2 - 29853643

AN - SCOPUS:85050700556

SN - 2159-8274

VL - 8

SP - 1112

EP - 1129

JO - Cancer Discovery

JF - Cancer Discovery

IS - 9

ER -

Organoid profiling identifies common responders to chemotherapy in pancreatic cancer

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