Abstract C57: Organoid profiling identifies common responders to chemotherapy in pancreatic cancer

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 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. Citation Format: Herve Tiriac, Pascal Belleau, Dannielle Engle, Dennis Plenker, Astrid Deschenes, Tim Somerville, Fieke Froeling, Richard Moffitt, Jennifer Knox, Alexander Krasnitz, Steven Gallinger, David Tuveson. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C57.