Brooke Heckel

Background: Cholangiocarcinoma (CCA) is an incredibly aggressive cancer of the biliary tree.¹ CCA can be subdivided into three subtypes based on tumor origin within the tree: Distal CCA, Perihilar CCA, and Intrahepatic CCA originating in the common bile duct, primary hepatic duct, and second-order bile ducts respectively.¹ Although this cancer is relatively rare with a yearly incidence rate of 0.35-2.0 cases per 100,000 in higher-oncome countries, the increasing incidence rate along with the alarmingly low survival rate of 7-20% makes CCAs an important cancer to understand and treat.^1,2 Unfortunately, CCAs have varying risk factors, symptoms, and morphology amongst the subtypes, making diagnosis and treatment very difficult for these patients.^1,2,4 Currently, there are two therapeutic approaches- surgical resection and chemotherapy. Surgical resection is the only approach that is curative, but about 23% of patients are diagnosed early enough to qualify for resection, and those that do qualify experience a high rate of reoccurrence after surgery.^1,2 Cisplatin and Gemcitabine are the first-line chemotherapeutics for patients who do not qualify for surgery, but this therapeutic approach shows very little promise in improving patient prognosis.^1,2 Improving accurate diagnosis and gaining a better understanding of the transcriptomics/signaling pathways that contribute to CCAs aggressive nature could improve patient prognosis. The rarity, intricacy, and aggressive nature of CCAs make this research very difficult. Utilizing an in-vitro model that accurately represents/replicates the patient’s own tumor could be the solution to overcoming these barriers and opening the door to new therapeutic approaches that can improve CCA prognosis.

Objective: In this narrative review, we explored the efficacy of utilizing patient-derived organoids as a diagnostic tool, a transcriptomic model, and high-throughput drug-screening tool for intrahepatic cholangiocarcinoma.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2023 using the following keywords: “cholangiocarcinoma”, “cholangiocarcinoma therapeutics”, “patient-derived organoids”, “intrahepatic cholangiocarcinoma organoid”.

Results: Studies showed patient-derived organoids had the ability to amplify a small tissue sample from patient biopsy and remain viable for over 1 year in appropriate culture medium.^5,6 In addition, patient-derived organoids showed the ability to express appropriate subtyping markers and appropriate transcriptomic changes- thus improving the barrier diagnosis and transcriptomic barriers.⁶ To narrow in on the last barrier, ineffective drug treatments, this review focused on a subset of CCA patients experiencing drug resistance. Prior therapeutic research found the fibroblast growth factor receptor (FGFR) to be a promising target for future therapeutics.⁷ Unfortunately, a population of patients showed partial and full resistance to the FGFR inhibitor drugs resulting in further searching for the cause of this resistance.⁷ Studies found FGFR fusion proteins contributing to the increased tumorigenesis and drug resistance. Secondary pathways were exposed, and fusion-positive organoids were used as a high-throughput drug screening to test varying dual inhibitor approaches.^8,9 FGFR/HDAC dual inhibition showed the greatest synergistic affects in decreasing tumor size and inhibiting target pathways in an ex-vivo environment.⁹ These organoids were then compared to an in-vivo study of the same drug interventions to prove the mimicry of the ex-vivo model to its in-vivo origin.⁹ Organoids proved to be directly translatable to the in-vivo cell line in terms of proliferation index.⁹ This final study proved patient-derived organoids to be an appropriate tool for high-throughput drug screening in a patient-safe ex-vivo environment.

Conclusions: Patient-derived organoids can be used as an in-vitro model to improve appropriate diagnosis, analyze genomic changes, and improve therapeutic R&D as a high-throughput drug screening tool. Through each of these mechanisms, patient-derived organoids can improve prognosis for CCA patients.

Works Cited:

1. Banales JM, Marin JJ, Lamarca A, et al. Cholangiocarcinoma 2020: The next horizon in mechanisms and management. Nature Reviews Gastroenterology & Hepatology. 2020;17(9):557-588. doi:10.1038/s41575-020-0310-z
2. Valle JW, Kelley RK, Nervi B, Oh D-Y, Zhu AX. Biliary Tract Cancer. The Lancet. 2021;397(10272):428-444. doi:10.1016/s0140-6736(21)00153-7
3. Lei S, Zheng R, Zhang S, et al. Global patterns of breast cancer incidence and mortality: A population‐based cancer registry data analysis from 2000 to 2020. Cancer Communications. 2021;41(11):1183-1194. doi:10.1002/cac2.12207
4. Forner A, Vidili G, Rengo M, Bujanda L, Ponz‐Sarvisé M, Lamarca A. Clinical presentation, diagnosis and staging of Cholangiocarcinoma. Liver International. 2019;39(S1):98-107. doi:10.1111/liv.14086
5. Saito Y, Muramatsu T, Kanai Y, et al. Establishment of patient-derived organoids and drug screening for biliary tract carcinoma. Cell Reports. 2019;27(4). doi:10.1016/j.celrep.2019.03.088
6. Lee HS, Han DH, Cho K, et al. Integrative analysis of multiple genomic data from intrahepatic cholangiocarcinoma organoids enables tumor subtyping. Nature Communications. 2023;14(1). doi:10.1038/s41467-023-35896-4
7. Cristinziano G, Porru M, Lamberti D, et al. FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma. Journal of Hepatology. 2021;75(2):351-362. doi:10.1016/j.jhep.2021.02.032
8. Wu Q, Zhen Y, Shi L, et al. EGFR inhibition potentiates FGFR inhibitor therapy and overcomes resistance in FGFR2 Fusion–positive cholangiocarcinoma. Cancer Discovery. 2022;12(5):1378-1395. doi:10.1158/2159-8290.cd-21-1168
9. Lidsky ME, Wang Z, Lu M, et al. Leveraging patient-derived models of FGFR2 fusion-positive intrahepatic cholangiocarcinoma to identify synergistic therapies. npj Precision Oncology. 2022;6(1). doi:10.1038/s41698-022-00320-5
10. Karakasheva TA, Gabre JT, Sachdeva UM, et al. Patient-derived organoids as a platform for modeling a patient’s response to chemoradiotherapy in esophageal cancer. Scientific Reports. 2021;11(1). doi:10.1038/s41598-021-00706-8