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

Research output: Contribution to journalArticle

61 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.

Original languageEnglish (US)
Pages (from-to)1112-1129
Number of pages18
JournalCancer Discovery
Volume8
Issue number9
DOIs
StatePublished - Sep 2018

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Organoids
Pancreatic Neoplasms
Drug Therapy
Therapeutics
Precision Medicine
Standard of Care
Oncogenes
Transcriptome
Biomarkers
Quality of Life

ASJC Scopus subject areas

  • Oncology

Cite this

Tiriac, H., Belleau, P., Engle, D. D., Plenker, D., Deschênes, A., Somerville, T. D. D., ... 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

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

In: Cancer Discovery, Vol. 8, No. 9, 09.2018, p. 1112-1129.

Research output: Contribution to journalArticle

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
Tiriac H, Belleau P, Engle DD, Plenker D, Deschênes A, Somerville TDD et al. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. Cancer Discovery. 2018 Sep;8(9):1112-1129. https://doi.org/10.1158/2159-8290.CD-18-0349
Tiriac, Hervé ; Belleau, Pascal ; Engle, Dannielle D. ; Plenker, Dennis ; Deschênes, Astrid ; Somerville, Tim D.D. ; Froeling, Fieke E.M. ; Burkhart, Richard A. ; Denroche, Robert E. ; Jang, Gun Ho ; Miyabayashi, Koji ; Young, C. Megan ; Patel, Hardik ; Ma, Michelle ; Lacomb, Joseph F. ; Palmaira, Randze Lerie D. ; Javed, Ammar A. ; Huynh, Jasmine C. ; Johnson, Molly ; Arora, Kanika ; Robine, Nicolas ; Shah, Minita ; Sanghvi, Rashesh ; Goetz, Austin B. ; Lowder, Cinthya Y. ; Martello, Laura ; Driehuis, Else ; Lecomte, Nicolas ; Askan, Gokce ; Iacobuzio-Donahue, Christine A. ; Clevers, Hans ; Wood, Laura D. ; Hruban, Ralph H. ; Thompson, Elizabeth ; Aguirre, Andrew J. ; Wolpin, Brian M. ; Sasson, Aaron ; Kim, Joseph ; Wu, Maoxin ; Bucobo, Juan Carlos ; Allen, Peter ; Sejpal, Divyesh V. ; Nealon, William ; Sullivan, James D. ; Winter, Jordan M. ; Gimotty, Phyllis A. ; Grem, Jean L ; DiMaio, Dominick J ; Buscaglia, Jonathan M. ; Grandgenett, Paul M. ; Brody, Jonathan R. ; Hollingsworth, Michael A ; O’kane, Grainne M. ; Notta, Faiyaz ; Kim, Edward ; Crawford, James M. ; Devoe, Craig ; Ocean, Allyson ; Wolfgang, Christopher L. ; Yu, Kenneth H. ; Li, Ellen ; Vakoc, Christopher R. ; Hubert, Benjamin ; Fischer, Sandra E. ; Wilson, Julie M. ; Moffitt, Richard ; Knox, Jennifer ; Krasnitz, Alexander ; Gallinger, Steven ; Tuveson, David A. / Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. In: Cancer Discovery. 2018 ; Vol. 8, No. 9. pp. 1112-1129.
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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

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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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