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Cancer Discov. 2018 Sep;8(9):1112-1129. doi: 10.1158/2159-8290.CD-18-0349. Epub 2018 May 31.

Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
2
Johns Hopkins University, Division of Hepatobiliary and Pancreatic Surgery, Baltimore, Maryland.
3
PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
4
Swiss Federal Institute of Technology Lausanne (EPFL), School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Laboratory of Tumor Heterogeneity and Stemness in Cancer, Lausanne, Switzerland.
5
Department of Medicine, Stony Brook University, Stony Brook, New York.
6
Memorial Sloan Kettering Cancer Center, New York, New York.
7
University of California, Davis, Comprehensive Cancer Center, Division of Hematology and Oncology, Sacramento, California.
8
New York Genome Center, New York, New York.
9
Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
10
SUNY Downstate Medical Center, Department of Medicine, New York, New York.
11
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands.
12
University Medical Center (UMC), Utrecht, the Netherlands.
13
Princess Maxime Center (PMC), Utrecht, the Netherlands.
14
Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
15
Dana-Farber Cancer Institute, Broad Institute, Boston, Massachusetts.
16
Department of Surgery, Stony Brook University, Stony Brook, New York.
17
Department of Pathology, Stony Brook University, Stony Brook, New York.
18
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Division of Gastroenterology, Hempstead, New York.
19
Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York.
20
Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania.
21
Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
22
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
23
University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffet Cancer Center, Omaha, Nebraska.
24
Wallace McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
25
Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York.
26
Division of Medical Oncology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York.
27
Weill Cornell Medical College, New York, New York.
28
Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
29
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
30
Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York.
31
PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. dtuveson@cshl.edu steven.gallinger@uhn.ca.
32
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
33
Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada.
34
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. dtuveson@cshl.edu steven.gallinger@uhn.ca.
#
Contributed equally

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.

Comment in

PMID:
29853643
PMCID:
PMC6125219
[Available on 2019-09-01]
DOI:
10.1158/2159-8290.CD-18-0349

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