Abstract LB-011: Patient-derived organoids may facilitate precision medicine in pancreatic cancer: Demonstrating feasibility in the context of a multi-center clinical trial
Authors: Seppälä Toni T. , Zimmerman Jacquelyn W. , Rozich Noah , Blair Alex , Javed Ammar , Cameron John L. , Burns William R. , He Jin , Tuveson David , Wolfgang Christopher L. , Ryan David P. , Kimmelman Alec , Herman Joseph M. , Messersmith Wells , Hong Theodore S. , Ting David T. , Burkhart Richard Andrew 
Published: September 2020

Background: Systemic disease control is the principle driver of prognosis in patients with pancreatic cancer (PDAC). Currently, there are no predictive biomarkers of clinical response to guide selection of an optimal treatment approach. Our work explores the logistics and feasibility of generating patient tumor-derived models to serve as biomarkers. Methods: Patients with borderline resectable or locally advanced PDAC enrolled to participate in a multi-institutional prospective, randomized, trial were eligible. Pretreatment core needle biopsies from diagnostic endoscopy were shipped via commercial post to a centralized organoid laboratory. Patient-specific organoids (PDO) were established as previously described by our group. Putative predictive biomarkers of clinical treatment response, including whole-exome sequencing (WES), RNA-sequencing, and pharmacotyping (chemotherapeutic sensitivity testing) were performed prospectively. Putative predictive biomarkers will be compared to clinical outcomes when approved by the trial's Data Safety Monitoring Board. Results: Approximately 40% (42/98) of patients participated in tissue acquisition for organoid development. Culture maturation can be described in three relevant phases: establishment, expansion, and characterization. The establishment phase describes the emergence of viable ductal organoid development in the setting of a culture being cleared of other components of the tumor microenvironment. During these first 3-5 passages, there are numerous potential pitfalls, including technical and logistical challenges. Out of 42, 26 (62%) PDOs were successfully established. Notably, the establishment phase appears to be an area of the greatest improvement, as the rates of successful establishment improve while the collaborative team builds experience. Expansion involves biomass accumulation in clean culture. Of those that succeeded in establishment, 77% (20/26) entered in expansion phase. We can currently report 15 PDOs having reached the characterization phase (WES, RNA-seq with subtyping, and/or pharmacotyping). Based on RNA expression profile, 10/14 were classified as classical and 4 as basal-like subtype. Mean time to pharmacotyping was 179 days. The PDOs showed a variable population distribution of sensitivity to standard-of-care chemotherapeutics (gemcitabine, paclitaxel, irinotecan, 5-FU, oxaliplatin). Conclusions: Developing a living organoid biobank from PDAC biopsies in a multi-center trial setting is a tractable approach in precision medicine initiatives. Amongst a collaborative team of physician scientists, the establishment phase is critical. PDOs from pre-treatment biopsies can be individually characterized within a clinically relevant time frame and unique tumor-specific ex vivo-derived therapeutic sensitivities can be assessed.

Citation Format: Toni T. Seppälä, Jacquelyn W. Zimmerman, Noah Rozich, Alex Blair, Ammar Javed, John L. Cameron, William R. Burns, Jin He, David Tuveson, Christopher L. Wolfgang, David P. Ryan, Alec Kimmelman, Joseph M. Herman, Wells Messersmith, Theodore S. Hong, David T. Ting, Richard Andrew Burkhart. Patient-derived organoids may facilitate precision medicine in pancreatic cancer: Demonstrating feasibility in the context of a multi-center clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-011.