University of California San Diego
Organoid profiling identifies common responders to chemotherapy in pancreatic cancer
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. (Tiriac, et al. Cancer Discovery 2018. DOI: 10.1158/2159-8290.CD-18-0349).
Dr. Tiriac has focused his research on building a clinically translatable cell modeling and therapeutics effort using patient-derived organoids at the Moores Cancer Center at UC San Diego. Over the past three years, Hervé has developed and optimized the procedures for high-efficiency generation and characterization of pancreatic cancer patient-derived organoids at Cold Spring Harbor Laboratory. Along with genotyping and expressions analysis, Hervé established a pharmacotyping platform to predict the efficacy of chemotherapeutic and targeted therapy and recently published the findings in Cancer Discovery (Tiriac et al., 2018). Hervé doctoral work with Dr. Tracy Johnson at UC San Diego focused on the coupling mechanisms of transcription and splicing in budding yeast. As a postdoctoral fellow, Hervé joined Dr. Tuveson at Cold Spring Harbor Laboratory where he focused on building novel mouse and human models of disease. Hervé will now work with Dr. Lowy and the clinical faculty at the Moores Cancer Center to validate organoid-based precision medicine approaches in prospective studies.View Month