Patient-derived Organoid Pharmacotyping Is A Clinically Tractable Strategy For Precision Medicine In Pancreatic Cancer
*Toni T Seppälä1, *Jacqueline Zimmerman1, *Noah S Rozich1, *Alex B Blair1, *Dwayne Thomas1, *Jonathan Teinor1, *Ammar A Javed1, John L Cameron1, *William R Burns1, *Jin He1, *David A Tuveson2, *Elizabeth M Jaffee1, Christopher L Wolfgang1, *Richard A Burkhart1
1Johns Hopkins Hospital, Baltimore, MD;2Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Patients with pancreatic cancer (PDAC) who undergo surgical resection and receive effective chemotherapy have the best chance of long-term survival. However, we lack predictive biomarkers to guide optimal treatment. Ex-vivo generation of patient-derived organoids for predictive pharmacotyping may benefit PDAC patients.
PDO cultures were established from surgical specimens and endoscopic biopsies, expanded in Matrigel, and used for high-throughput drug testing (pharmacotyping). Efficacy of standard-of-care chemotherapeutics (gemcitabine, paclitaxel, irinotecan, 5-FU, oxaliplatin) was assessed by measuring cell viability during a five-day incubation.
A framework for rapid pharmacotyping of PDOs was established at academic medical centers. Biospecimens obtained remotely and shipped to a central biorepository maintain viability and allowed generation of PDOs with 76% success. Early cultures maintain the clonal heterogeneity seen in PDAC with similar phenotypes (cystic-solid). Late cultures exhibit a dominant clone with a pharmacotyping profile similar to early passages. The biomass required for accurate pharmacotyping can be minimized by leveraging a high-throughput technology. Twenty cultures were pharmacotyped to derive a population distribution of chemotherapeutic sensitivity at our center (Figure1). Pharmacotyping rapidly-expanded PDOs for clinical decision-making was completed in a median of 43 (range 22-76) days.
Rapid development of PDOs from patients undergoing surgery for PDAC can reliably occur within the perioperative recovery period, enabling pharmacotyping to guide post-operative chemotherapeutic selection. Studies validating PDOs as a promising predictive biomarker are ongoing.
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