Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Hervé Tiriac(Cold Spring Harbor Laboratory), Pascal Belleau(Cold Spring Harbor Laboratory), Dannielle D. Engle(Cold Spring Harbor Laboratory), Dennis Plenker(Cold Spring Harbor Laboratory), Astrid Deschênes(Cold Spring Harbor Laboratory), Tim D.D. Somerville(Cold Spring Harbor Laboratory), Fieke E. M. Froeling(Cold Spring Harbor Laboratory), Richard A. Burkhart(University of Baltimore), Robert E. Denroche(Ontario Institute for Cancer Research), Gun-Ho Jang(Ontario Institute for Cancer Research), Koji Miyabayashi(Cold Spring Harbor Laboratory), C. Megan Young(Cold Spring Harbor Laboratory), Hardik J. Patel(Cold Spring Harbor Laboratory), Michelle Ma(Cold Spring Harbor Laboratory), Joseph F. LaComb(Stony Brook University), Randze Lerie D. Palmaira(Kettering University), Ammar A. Javed(University of Baltimore), Jasmine C. Huynh(University of California Davis Medical Center), Molly Johnson(New York Genome Center), Kanika Arora(New York Genome Center), Nicolas Robine(New York Genome Center), Minita Shah(New York Genome Center), Rashesh Sanghvi(New York Genome Center), Austin Goetz(Thomas Jefferson University), Cinthya Y. Lowder(Thomas Jefferson University), Laura Martello(SUNY Downstate Health Sciences University), Else Driehuis(Royal Netherlands Academy of Arts and Sciences), Nicolas Lecomte(Kettering University), Gökçe Aşkan(Kettering University), Christine A. Iacobuzio–Donahue(Kettering University), Hans Clevers(Royal Netherlands Academy of Arts and Sciences), Laura D. Wood(Johns Hopkins University), Ralph H. Hruban(Johns Hopkins University), Elizabeth D. Thompson(Johns Hopkins University), Andrew J. Aguirre(Dana-Farber Cancer Institute), Brian M. Wolpin(Dana-Farber Cancer Institute), Aaron R. Sasson(Stony Brook University), Joseph Kim(Stony Brook University), Maoxin Wu(Stony Brook University), Juan Carlos Bucobo(Stony Brook University), Peter J. Allen(Kettering University), Divyesh V. Sejpal(Hofstra University), William H. Nealon(Donald & Barbara Zucker School of Medicine at Hofstra/Northwell), J. D. Sullivan(Donald & Barbara Zucker School of Medicine at Hofstra/Northwell), Jordan M. Winter(Thomas Jefferson University), Phyllis A. Gimotty(University of Pennsylvania), Jean L. Grem(Nebraska Medical Center), Dominick J. DiMaio(University of Nebraska Medical Center), Jonathan M. Buscaglia(Stony Brook University), Paul M. Grandgenett(Nebraska Medical Center), Jonathan R. Brody(Thomas Jefferson University), Michael A. Hollingsworth(Nebraska Medical Center), Grainne M. O’Kane(Princess Margaret Cancer Centre), Faiyaz Notta(Ontario Institute for Cancer Research), Edward Kim(University of California Davis Medical Center), James M. Crawford(Donald & Barbara Zucker School of Medicine at Hofstra/Northwell), Craig Devoe(Donald & Barbara Zucker School of Medicine at Hofstra/Northwell), Allyson J. Ocean(Cornell University), Christopher L. Wolfgang(University of Baltimore), Kenneth H. Yu(Kettering University), Ellen Li(Stony Brook University), Christopher R. Vakoc(Cold Spring Harbor Laboratory), Benjamin Hubert(New York Genome Center), Sandra E. Fischer(University Health Network), Julie M. Wilson(Ontario Institute for Cancer Research), Richard A. Moffitt(Stony Brook University), Jennifer J. Knox(Princess Margaret Cancer Centre), Alexander Krasnitz(Cold Spring Harbor Laboratory), Steven Gallinger(Ontario Institute for Cancer Research), David A. Tuveson(Cold Spring Harbor Laboratory)
Cancer Discovery
May 31, 2018
10.1158/2159-8290.cd-18-0349
Cited by 1,088Open Access
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Abstract

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

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