Data from Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer
Authors: 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. 
Published: March 2024

<div>Abstract<p>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.</p><p><b>Significance:</b> 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. <i>Cancer Discov; 8(9); 1112–29. ©2018 AACR.</i></p><p><i>See related commentary by Collisson, p. 1062</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 1047</i></p></div>