Related Experiment Video
Updated: Nov 13, 2025
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Molecular and morphological changes induced by ivosidenib correlate with efficacy in mutant-IDH1 cholangiocarcinoma
Elia Aguado-Fraile1, Ania Tassinari1, Yuko Ishii1
1Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Abstract:
Background: IDH1 mutations occur in approximately 13% of intrahepatic cholangiocarcinomas (IHCCs). The oral, targeted, mutant IDH1 (mIDH1) inhibitor ivosidenib (AG-120) suppresses production of the oncometabolite D-2-hydroxyglutarate, promoting disease stabilization and improved progression-free survival (PFS) in mIDH1 IHCC. Materials & methods: Harnessing matched baseline and on-treatment biopsies, we investigate the potential mechanisms underlying ivosidenib's efficacy. Results: mIDH1 inhibition leads to decreased cytoplasm and expression of hepatocyte lineage markers in patients with prolonged PFS. These findings are accompanied by downregulation of biliary fate, cell cycle progression and AKT pathway activity. Conclusion: Ivosidenib stimulates a hepatocyte differentiation program in mIDH1 IHCC, a phenotype associated with clinical benefit. mIDH1 inhibition could be a paradigm for differentiation-based therapy in solid tumors. Clinical trial registration: NCT02073994 (ClinicalTrials.gov).
Insights
Ivosidenib, a targeted therapy for intrahepatic cholangiocarcinoma with IDH1 mutations, promotes cancer cell differentiation into normal liver cells. This mechanism is linked to improved patient outcomes and disease stabilization.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Intrahepatic cholangiocarcinoma (IHCC) harbors IDH1 mutations in approximately 13% of cases.
- Ivosidenib (AG-120) is an oral targeted inhibitor of mutant IDH1 (mIDH1).
- Ivosidenib suppresses the oncometabolite D-2-hydroxyglutarate, showing potential for disease stabilization and improved progression-free survival (PFS) in mIDH1 IHCC.
Purpose of the Study:
- To investigate the molecular mechanisms underlying ivosidenib's efficacy in mIDH1 IHCC.
- To identify biomarkers associated with response to ivosidenib treatment.
Main Methods:
- Analysis of matched baseline and on-treatment tumor biopsies.
- Assessment of cellular markers, lineage expression, and pathway activity.
Main Results:
- Ivosidenib treatment led to decreased cytoplasm and expression of hepatocyte lineage markers in patients with prolonged PFS.
- Observed downregulation of biliary fate, cell cycle progression, and AKT pathway activity.
- Hepatocyte differentiation phenotype correlated with clinical benefit.
Conclusions:
- Ivosidenib induces a hepatocyte differentiation program in mIDH1 IHCC.
- This differentiation-based mechanism is associated with clinical benefit.
- mIDH1 inhibition represents a potential paradigm for differentiation therapy in solid tumors.
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