Organoid profiling identifies common responders to chemotherapy in pancreatic cancer
Hervé Tiriac,Pascal Belleau,Dannielle D. Engle,Dennis Plenker,Astrid Deschênes,Tim D.D. Somerville,Fieke E. M. Froeling,Richard A. Burkhart,Robert E. Denroche,Gun-Ho Jang,Koji Miyabayashi,C. Megan Young,C. Megan Young,Hardik Patel,Michelle Ma,Joseph F. LaComb,Randze Lerie Palmaira,Ammar A. Javed,Jasmine Huynh,Molly E. Johnson,Kanika Arora,Nicolas Robine,Minita Shah,Rashesh Sanghvi,Austin Goetz,Cinthya Y. Lowder,Laura A. Martello,Else Driehuis,Nicolas Lecomte,Gokce Askan,Christine A. Iacobuzio-Donahue,Hans Clevers,Laura D. Wood,Ralph H. Hruban,Elizabeth D. Thompson,Andrew J. Aguirre,Brian M. Wolpin,Aaron R. Sasson,Joseph Kim,Maoxin Wu,Juan Carlos Bucobo,Peter J. Allen,Divyesh V. Sejpal,William Nealon,James Sullivan,Jordan M. Winter,Phyllis A. Gimotty,Jean L. Grem,Dominick J. DiMaio,Jonathan M. Buscaglia,Paul M. Grandgenett,Jonathan R. Brody,Michael A. Hollingsworth,Grainne M. O'Kane,Faiyaz Notta,Edward J. Kim,James M. Crawford,Craig Devoe,Allyson J. Ocean,Christopher L. Wolfgang,Kenneth H. Yu,Ellen Li,Christopher R. Vakoc,Benjamin Hubert,Sandra Fischer,Sandra Fischer,Julie M. Wilson,Richard A. Moffitt,Jennifer J. Knox,Alexander Krasnitz,Steven Gallinger,Steven Gallinger,Steven Gallinger,David A. Tuveson +73 more
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TLDR
A pancreatic cancer patient-derived organoid (PDO) library is generated that recapitulates the mutational spectrum and transcriptional subtypes of primary Pancreatic cancer and proposes that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.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 find that PDO therapeutic profiles paralleled patient outcomes and that PDOs enable longitudinal assessment of chemo-sensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemo-sensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemo-refractory 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.read more
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Cancer modeling meets human organoid technology.
TL;DR: Emerging evidence indicates that organoids can be used to accurately predict drug responses in a personalized treatment setting, and the current state and future prospects of the rapidly evolving tumor organoid field are reviewed.
Journal ArticleDOI
Optimizing the outcomes of pancreatic cancer surgery
TL;DR: The safety and efficacy of pancreatic cancer surgery have improved considerably in the past decade, enabling perioperative mortality of around 3% and 5-year survival approaching 30–40% after resection and chemotherapy.
Journal ArticleDOI
Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer
Kirsten L. Bryant,Clint A. Stalnecker,Daniel Zeitouni,Jennifer E. Klomp,Sen Peng,Andrey P. Tikunov,Venugopal Gunda,Mariaelena Pierobon,Adele Waters,Samuel D. George,Garima Tomar,Björn Papke,G. Aaron Hobbs,Liang Yan,Tikvah K. Hayes,J. Nathaniel Diehl,Gennifer D. Goode,Nina V. Chaika,Yingxue Wang,Guo-Fang Zhang,Agnieszka K. Witkiewicz,Erik S. Knudsen,Emanuel F. Petricoin,Pankaj K. Singh,Jeffrey M. Macdonald,Nhan L. Tran,Costas A. Lyssiotis,Haoqiang Ying,Alec C. Kimmelman,Adrienne D. Cox,Channing J. Der +30 more
TL;DR: It is concluded that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.
Journal ArticleDOI
Stem cell fate in cancer growth, progression and therapy resistance
TL;DR: Evidence showing that activation of stem cell programmes in cancers can lead to progression, therapy resistance and metastatic growth and that targeting these attributes may enable better control over a difficult disease is considered.
Journal ArticleDOI
Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients.
Salo N. Ooft,Fleur Weeber,Krijn K. Dijkstra,Chelsea M. McLean,Sovann Kaing,Erik van Werkhoven,Luuk J. Schipper,L.R. Hoes,Daniel J. Vis,Joris van de Haar,Warner Prevoo,Petur Snaebjornsson,Daphne L. van der Velden,Michelle Klein,Myriam Chalabi,Henk Boot,Monique E. van Leerdam,Haiko J. Bloemendal,Laurens V. Beerepoot,Lodewyk F. A. Wessels,Lodewyk F. A. Wessels,Edwin Cuppen,Hans Clevers,Emile E. Voest +23 more
TL;DR: An in vitro test based on patient-derived tumor organoids (PDOs) from metastatic lesions to identify nonresponders to standard-of-care chemotherapy in colorectal cancer (CRC) is developed and the feasibility of generating and testing PDOs for evaluation of sensitivity to chemotherapy is shown.
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