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Patient-Derived Organoids for Personalized Drug Screening in Intrahepatic CCA

2020 Year in Review: Cholangiocarcinoma — December 19, 2020

Emerging data suggest that patient-derived 3-dimensional organoid model of intrahepatic CCA may allow personalized drug screening for active single agents or drug combinations similar to patient-derived xenograft models.

Treatment outcomes for patients with unresectable intrahepatic CCA is suboptimal, with several novel genetically targeted therapeutics being developed. Preclinical models such as patient-derived xenograft (PDX) models are being used to understand cancer biology and aid in drug discovery. At the American Society of Clinical Oncology (ASCO) 2020 Gastrointestinal Cancers Symposium, a report of a patient-derived 3-dimensional organoid (PDXO) culture of intrahepatic CCA that enabled individualized identification of active single agents or drug combinations was presented and summarized here.

Freshly resected intrahepatic CCA samples were used to generate PDXs and PDXOs, which are small spheroidal clusters of tumor cells grown in vitro. A high-throughput drug screening platform using artificial intelligence–enhanced robotics was employed to identify and distribute single, uniformly sized PDXOs into 384 well ultra-low adherent plates. This was followed by delivering candidate drugs from a 34-drug panel using a TECAN D300e drug dispenser.

Whole-exome sequencing showed concordance of characteristic genomic features such as alterations in IDH1, PBRM1, ATM, ARIDIA, KRAS, and KIT, among primary tumor, PDX, and PDXO models. Drug response analysis of intrahepatic CCA PDXOs showed that drug responses were specific to individual tumors. Notably, this PDXO drug screening model identified mammalian target of rapamycin (mTOR) complex-1 inhibitors to have the most antitumor activity in PDXOs from all patients, suggesting the importance of the mTOR pathway in the pathogenesis of intrahepatic CCA. Also, there was concordance between responses of the organoid to the mTOR inhibitor INK128 and the PDX from the same patient, indicating that PDXOs can be used to predict in vivo drug responses. Patient-specific synergy between INK128 and gemcitabine was demonstrated in PDXO and in vivo PDX models of the same patient.

These results indicate that patient-specific organoid models of intrahepatic CCA may predict patient responses to drugs similar to PDX models, and facilitate economical patient-specific, high-throughput drug screening that could inform clinical practice and improve patient outcomes. 

Source: Antonia RJ, et al. J Clin Oncol. 2020;38(4_suppl). Abstract 581.

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