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Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.

Authors :
Tiriac H
Belleau P
Engle DD
Plenker D
DeschĂȘnes A
Somerville TDD
Froeling FEM
Burkhart RA
Denroche RE
Jang GH
Miyabayashi K
Young CM
Patel H
Ma M
LaComb JF
Palmaira RLD
Javed AA
Huynh JC
Johnson M
Arora K
Robine N
Shah M
Sanghvi R
Goetz AB
Lowder CY
Martello L
Driehuis E
LeComte N
Askan G
Iacobuzio-Donahue CA
Clevers H
Wood LD
Hruban RH
Thompson E
Aguirre AJ
Wolpin BM
Sasson A
Kim J
Wu M
Bucobo JC
Allen P
Sejpal DV
Nealon W
Sullivan JD
Winter JM
Gimotty PA
Grem JL
DiMaio DJ
Buscaglia JM
Grandgenett PM
Brody JR
Hollingsworth MA
O'Kane GM
Notta F
Kim E
Crawford JM
Devoe C
Ocean A
Wolfgang CL
Yu KH
Li E
Vakoc CR
Hubert B
Fischer SE
Wilson JM
Moffitt R
Knox J
Krasnitz A
Gallinger S
Tuveson DA
Source :
Cancer discovery [Cancer Discov] 2018 Sep; Vol. 8 (9), pp. 1112-1129. Date of Electronic Publication: 2018 May 31.
Publication Year :
2018

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 .<br /> (©2018 American Association for Cancer Research.)

Details

Language :
English
ISSN :
2159-8290
Volume :
8
Issue :
9
Database :
MEDLINE
Journal :
Cancer discovery
Publication Type :
Academic Journal
Accession number :
29853643
Full Text :
https://doi.org/10.1158/2159-8290.CD-18-0349