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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.
Affiliation
  • Tiriac H; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • Belleau P; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • Engle DD; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • Plenker D; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • Deschênes A; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • Somerville TDD; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • Froeling FEM; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • Burkhart RA; Johns Hopkins University, Division of Hepatobiliary and Pancreatic Surgery, Baltimore, Maryland.
  • Denroche RE; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Jang GH; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Miyabayashi K; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • Young CM; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • Patel H; 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.
  • Ma M; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • LaComb JF; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • Palmaira RLD; Department of Medicine, Stony Brook University, Stony Brook, New York.
  • Javed AA; Memorial Sloan Kettering Cancer Center, New York, New York.
  • Huynh JC; Johns Hopkins University, Division of Hepatobiliary and Pancreatic Surgery, Baltimore, Maryland.
  • Johnson M; University of California, Davis, Comprehensive Cancer Center, Division of Hematology and Oncology, Sacramento, California.
  • Arora K; New York Genome Center, New York, New York.
  • Robine N; New York Genome Center, New York, New York.
  • Shah M; New York Genome Center, New York, New York.
  • Sanghvi R; New York Genome Center, New York, New York.
  • Goetz AB; New York Genome Center, New York, New York.
  • Lowder CY; Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • Martello L; Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • Driehuis E; SUNY Downstate Medical Center, Department of Medicine, New York, New York.
  • LeComte N; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands.
  • Askan G; University Medical Center (UMC), Utrecht, the Netherlands.
  • Iacobuzio-Donahue CA; Memorial Sloan Kettering Cancer Center, New York, New York.
  • Clevers H; Memorial Sloan Kettering Cancer Center, New York, New York.
  • Wood LD; Memorial Sloan Kettering Cancer Center, New York, New York.
  • Hruban RH; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands.
  • Thompson E; University Medical Center (UMC), Utrecht, the Netherlands.
  • Aguirre AJ; Princess Maxime Center (PMC), Utrecht, the Netherlands.
  • Wolpin BM; Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
  • Sasson A; Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
  • Kim J; Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
  • Wu M; Dana-Farber Cancer Institute, Broad Institute, Boston, Massachusetts.
  • Bucobo JC; Dana-Farber Cancer Institute, Broad Institute, Boston, Massachusetts.
  • Allen P; Department of Surgery, Stony Brook University, Stony Brook, New York.
  • Sejpal DV; Department of Surgery, Stony Brook University, Stony Brook, New York.
  • Nealon W; Department of Pathology, Stony Brook University, Stony Brook, New York.
  • Sullivan JD; Department of Medicine, Stony Brook University, Stony Brook, New York.
  • Winter JM; Memorial Sloan Kettering Cancer Center, New York, New York.
  • Gimotty PA; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Division of Gastroenterology, Hempstead, New York.
  • Grem JL; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York.
  • DiMaio DJ; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York.
  • Buscaglia JM; Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • Grandgenett PM; Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania.
Cancer Discov ; 8(9): 1112-1129, 2018 09.
Article in En | MEDLINE | ID: mdl-29853643
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancreatic Neoplasms / Organoids / Gene Expression Profiling / Gene Regulatory Networks / Antineoplastic Agents Type of study: Observational_studies / Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Cancer Discov Year: 2018 Type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancreatic Neoplasms / Organoids / Gene Expression Profiling / Gene Regulatory Networks / Antineoplastic Agents Type of study: Observational_studies / Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Cancer Discov Year: 2018 Type: Article