Mutations in the isocitrate dehydrogenase (IDH)1 and IDH2 enzymes are among the most common genetic alterations in intrahepatic cholangiocarcinoma (CCA) and are present in approximately 20% of patients. IDH proteins are enzymes involved in diverse cellular processes, including histone demethylation and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (also called citric acid or Krebs) cycle.
The mutated IDH protein exhibits aberrant enzymatic function, reducing alpha-ketoglutarate (αKG, which plays a crucial role in cellular energy metabolism) to the oncometabolite 2-hydroxyglutarate (2-HG). The 2-HG competitively inhibits αKG-dependent histone and DNA demethylating enzymes, thereby altering chromatin regulation. Chromatin plays a crucial role in regulating gene expression.
The first-in-class small-molecule ivosidenib (Tibsovo), a selective IDH1 inhibitor, has shown benefit in phase 1 and 2 clinical trials of patients with intrahepatic CCA and IDH1 mutation.
The data from the 2 clinical trials were convincing enough for the National Comprehensive Cancer Network (NCCN) to add ivosidenib to its updated guidelines of hepatobiliary cancers that was published on June 1, 2020.
The NCCN Drugs & Biologics Compendium recommendation specifically states that the drug is approved for “Subsequent treatment as a single-agent…for progression on or after systemic treatment for unresectable or metastatic disease with an isocitrate dehydrogenase-1 (IDH1) mutation.”
Meng-Ju Wu, PhD, MS, Postdoctoral Research Fellow, Center for Cancer Research, Massachusetts General Hospital, Boston, and colleagues explored the relationship between ivosidenib treatment and the vehicle therapy, and the mechanism underlying the response to IDH1 inhibition, using a proprietary, first genetically engineered mouse model of intrahepatic CCA with IDH1 mutation. Dr Wu discussed the results at an oral presentation during the 2020 American Association for Cancer Research (AACR) annual meeting.
In addition to reducing the overall tumor burden—a reduction of tumor-produced 2-HG >85% was also observed—the researchers discovered that ivosidenib also promotes hepatocyte-cell differentiation (2-HG hinders hepatic progenitor-cell differentiation) to mature hepatocytes. Dr Wu presented the results at the 2020 AACR annual meeting.
Dr Wu and colleagues also detected an enhanced immune response to ivosidenib in this mouse model. They noted an increased recruitment of CD8-positive T-cells to the tumors, which is important because the tumor microenvironment in intrahepatic CCA dampens the activity of CD8-positive T-cells and other immune cells, such as natural killer cells and dendritic cells. There was pronounced induction of immune stimulatory interferon signaling, and PD-L1 expression was upregulated.
At the AACR meeting, Dr Wu concluded, “My study provides the first faithful genetically engineered mouse model of IDH1-mutated intrahepatic cholangiocarcinoma. It will elucidate the tumor maintenance program driven by IDH1 mutation, defining the impact of this oncogene on tumor-cell epigenetic programs and tumor-immune microenvironment interplay. The work provides a strong preclinical rationale for combination treatment strategies involving ivosidenib in patients with intrahepatic cholangiocarcinoma and IDH1 mutation.”
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