| Literature DB >> 29853643 |
Pascal Belleau1, Dannielle D Engle1, Hervé Tiriac1, Dennis Plenker1, Astrid Deschênes1, Tim D D Somerville1, Fieke E M Froeling1, Richard A Burkhart2, Robert E Denroche3, Gun-Ho Jang3, Koji Miyabayashi1, C Megan Young1,4, Hardik Patel1, Michelle Ma1, Joseph F LaComb5, Randze Lerie D Palmaira6, Ammar A Javed2, Jasmine C Huynh7, Molly Johnson8, Kanika Arora8, Nicolas Robine8, Minita Shah8, Rashesh Sanghvi8, Austin B Goetz9, Cinthya Y Lowder9, Laura Martello10, Else Driehuis11,12, Nicolas LeComte6, Gokce Askan6, Christine A Iacobuzio-Donahue6, Hans Clevers11,12,13, Laura D Wood14, Ralph H Hruban14, Elizabeth Thompson14, Andrew J Aguirre15, Brian M Wolpin15, Aaron Sasson16, Joseph Kim16, Maoxin Wu17, Juan Carlos Bucobo5, Peter Allen6, Divyesh V Sejpal18, William Nealon19, James D Sullivan19, Jordan M Winter9, Phyllis A Gimotty20, Jean L Grem21, Dominick J DiMaio22, Jonathan M Buscaglia5, Paul M Grandgenett23, Jonathan R Brody9, Michael A Hollingsworth23, Grainne M O'Kane24, Faiyaz Notta3, Edward Kim7, James M Crawford25, Craig Devoe26, Allyson Ocean27, Christopher L Wolfgang2, Kenneth H Yu6, Ellen Li5, Christopher R Vakoc1, Benjamin Hubert8, Sandra E Fischer28,29, Julie M Wilson3, Richard Moffitt16,30, Jennifer Knox24, Alexander Krasnitz1, Steven Gallinger31,24,32,33, David A Tuveson34.
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. 1062This article is highlighted in the In This Issue feature, p. 1047. ©2018 American Association for Cancer Research.Entities:
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Year: 2018 PMID： 29853643 PMCID： PMC6125219 DOI： 10.1158/2159-8290.CD-18-0349
Source DB: PubMed Journal: Cancer Discov ISSN： 2159-8274 Impact factor: 38.272