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Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.
- 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.)
- Subjects :
- Antineoplastic Agents therapeutic use
Drug Resistance, Neoplasm drug effects
Drug Screening Assays, Antitumor
Gene Expression Regulation, Neoplastic drug effects
Humans
Molecular Targeted Therapy
Organoids chemistry
Organoids cytology
Pancreatic Neoplasms drug therapy
Pancreatic Neoplasms genetics
Precision Medicine
Prospective Studies
Sequence Analysis, RNA
Standard of Care
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Gene Expression Profiling methods
Gene Regulatory Networks drug effects
Organoids drug effects
Pancreatic Neoplasms pathology
Subjects
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