학술논문

Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.
Document Type
article
Source
Cancer discovery. 8(9)
Subject
Organoids
Tumor Cells
Cultured
Humans
Pancreatic Neoplasms
Antineoplastic Agents
Drug Screening Assays
Antitumor
Prospective Studies
Gene Expression Profiling
Sequence Analysis
RNA
Gene Expression Regulation
Neoplastic
Drug Resistance
Neoplasm
Gene Regulatory Networks
Molecular Targeted Therapy
Standard of Care
Precision Medicine
Genetics
Pancreatic Cancer
Rare Diseases
Digestive Diseases
Orphan Drug
Cancer
Detection
screening and diagnosis
Development of treatments and therapeutic interventions
4.1 Discovery and preclinical testing of markers and technologies
5.1 Pharmaceuticals
Good Health and Well Being
Oncology and Carcinogenesis
Language
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.