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

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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.

Originele taal-2	Engels
Pagina's (van-tot)	1112-1129
Aantal pagina's	18
Tijdschrift	Cancer Discovery
Volume	8
Nummer van het tijdschrift	9
DOI's	https://doi.org/10.1158/2159-8290.CD-18-0349
Status	Gepubliceerd - sep. 2018
Extern gepubliceerd	Ja

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10.1158/2159-8290.CD-18-0349

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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{e9d01cbd7dbc41cd837722cc4c07b884,

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.",

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 = "Publisher Copyright: {\textcopyright}2018 American Association for Cancer Research.",

year = "2018",

month = sep,

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, nr. 9, blz. 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.

PY - 2018/9

Y1 - 2018/9

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.

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.

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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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