Abstract 3929: Patient-derived pancreatic cancer organoids as in-vitro cancer models for personalizing therapy

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive solid tumor. Unfortunately, patients with this disease have not benefited from the advances in precision medicine seen in other malignancies. The lack of actionable mutations as well as predictive biomarkers has hampered progress in this area. Combination therapy remains the cornerstone of systemic treatment, with FOLFIRINOX being the most effective therapeutic regimen in PDAC. However, it is clear that only subset of patients are responsive, and the toxicities of this 4-drug combination are intolerable to many patients particularly in the adjuvant setting. There is a clear need for more personalized rational drug combinations that are optimized to maximize efficacy while minimizing toxicity. We have established a protocol for the generation of PDAC organoids from endoscopic ultrasound biopsies for personalizing systemic therapy based on the principle of phenotype driven oncology. Organoids generated are analyzed for KRAS and p53 mutations to confirm their tumor origin. By applying a phenotypic optimization platform (QPOP) on these organoids, we are able to identify optimized drug combinations from a pool of both FDA-approved and preclinical drugs. As expected, FOLFIRINOX did not always rank high by treatment efficacy suggesting that alternative treatment may be more beneficial for these patients. In addition, we identified that the efficacy of FOLFIRINOX was driven by two-drug synergistic combinations which varied between patients. This can potentially advise modifications to this regimen when toxicity arises. From a discovery perspective, our platform has the capability of deriving novel drug combinations. The combination of gemcitabine and Abraxane with a WEE1-inhibitor was found to be synergistic in selected PDAC patients. Furthermore, patients with similar drug response profiles can be studied together to identify predictive markers of sensitivity. To demonstrate that this platform can indeed be applied to prospectively recommend treatment strategies for patients with progressive disease on first-line chemotherapy, we are establishing a clinical trial to personalize second-line therapy, with the endpoint of overall response rate. Overall, by combining patient-derived organoids with rational optimized drug combinations, we aim to personalize therapy for patients with PDAC to improve overall survival. Citation Format: Claire Alexandra Zhen Chew, Li Min Tay, Lissa Hooi, Edward Kai-Hua Chow, Glenn K. Bonney, Shing Leng Chan. Patient-derived pancreatic cancer organoids as in-vitro cancer models for personalizing therapy [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 3929.