The Lynx Group
Cholangiocarcinoma News

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.

Related Items

Ivosidenib Approved for Advanced or Metastatic Cholangiocarcinoma
Web Exclusives
Ivosidenib has been approved by the FDA for adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 mutation as detected by an FDA-approved test.
Recent Developments in Genomic-Driven Therapies for Cholangiocarcinoma
June/July 2021, Vol 2, No 2
Personalized medicine has expanded the treatment options for patients with cholangiocarcinoma (CCA). At the 2021 Annual Meeting of the Cholangiocarcinoma Foundation (CCF), Ghassan K. Abou-Alfa, MD, MBA, Professor of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, discussed recent developments in personalized therapies, highlighting genomic alterations that are informing the new therapies for patients with CCA.
FDA Grants Accelerated Approval to Infigratinib for Metastatic Cholangiocarcinoma
June/July 2021, Vol 2, No 2
The FDA granted accelerated approval to the kinase inhibitor infigratinib (Truseltiq) for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma (CCA) that harbors an FGFR2 fusion or other rearrangement.
Futibatinib in Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Rearrangements: Primary Results of FOENIX-CCA2 Presented at AACR 2021
June/July 2021, Vol 2, No 2
The primary results of the phase 2 FOENIX-CCA2 clinical trial of futibatinib in patients with previously treated intrahepatic cholangiocarcinoma (CCA) and FGFR2 fusions or rearrangements were presented by Lipika Goyal, MD, MPhil, Assistant Professor of Medicine, Massachusetts General Hospital, Boston, at the 2021 Annual Meeting of the American Association for Cancer Research (AACR).
Truseltiq (Infigratinib) New Targeted Therapy FDA Approved for Advanced or Metastatic Cholangiocarcinoma Harboring FGFR2 Alterations
By Loretta Fala
June/July 2021, Vol 2, No 2
Cholangiocarcinoma (CCA) represents a group of heterogeneous cancers that originate in the bile ducts that connect the liver and gallbladder to the small intestine. Although the exact prevalence of CCA is unknown, CCA is a rare cancer; approximately 8000 new cases of CCA are diagnosed annually in the United States.
Incorporating FGFR Inhibitors into the Treatment Paradigm for Cholangiocarcinoma: Current Concepts and Future Directions
By Mitesh J. Borad, MD; Milind M. Javle, MD; Michael Morse, MD, FACP, MHS; Lewis R. Roberts, MB, ChB, PhD
June/July 2021, Vol 2, No 2
On January 15, 2021, experts in the management of patients with cholangiocarcinoma (CCA) convened for a virtual accredited continuing education satellite symposium held during the 2021 annual meeting of the American Society of Clinical Oncology Gastrointestinal Cancers Symposium. The goal was to educate healthcare providers on various aspects of CCA, including epidemiology, current standards of care, unmet clinical needs, the safety and efficacy of fibroblast growth factor receptor (FGFR) inhibitors as second-line therapy, and practical approaches to incorporating FGFR inhibitors into the treatment paradigm for the disease.
The Latest Research in Biliary Tract Cancers Presented at ASCO GI 2021
March 2021, Vol 2, No 1
At the CCA Summit held during the 2021 ASCO Gastrointestinal (GI) Cancers Symposium, Rachna T. Shroff, MD, MS, Chief, Section of GI Medical Oncology, University of Arizona Cancer Center, Tucson, discussed 15 clinical trials that were presented at the ASCO GI Cancers Symposium on cholangiocarcinoma (CCA) and hepatobiliary diseases. She highlighted key advances related to chemotherapy, targeted therapies, and biomarkers in the management of biliary tract cancers, including CCA.
Targeted Therapies in Cholangiocarcinoma: Next-Generation Sequencing Is a Must
December 2020, Vol 1, No 3
The recent FDA approval of the first FGFR inhibitor, pemigatinib (Pemazyre), and the positive results from the phase 3 study of the first IDH1 inhibitor, ivosidenib (Tibsovo), represent major breakthroughs in the treatment of patients with cholangiocarcinoma (CCA), a rare cancer associated with poor outcomes. However, the duration of response with these agents is still relatively short.
FGFR Inhibition in Cholangiocarcinoma: Overcoming Acquired Resistance
December 2020, Vol 1, No 3
In April 2020, the FDA granted accelerated approval to pemigatinib (Pemazyre), the first targeted therapy for cholangiocarcinoma (CCA). The FGFR inhibitor was approved for adults with CCA and FGFR2 fusion.
Emerging Molecular Targets in Cholangiocarcinoma: IDH1, HER2, BRAF, and Beyond
December 2020, Vol 1, No 3
Targeted therapy has improved survival for patients with cancer across a broad spectrum of disease sites, but until recently, progress has been slow in the treatment of patients with cholangiocarcinoma (CCA).

Subscribe to CCA News

Stay up to date with personalized medicine by subscribing to receive the free CCA News print publication or weekly e‑Newsletter.

I'd like to receive: