Target exposure and pharmacodynamics study of the indoleamine 2,3-dioxygenase-1 (IDO-1) inhibitor epacadostat in the CT26 mouse tumor model

Abstract

Indoleamine-2,3-dioxygénase (IDO1) is an enzyme which converts tryptophan (Trp) into kynurenine (Kyn). Having a critical role in tumor immune escape by decreasing Trp and increasing Kyn levels in the microenvironment, IDO1 was one of the first targets for small molecules drug discovery in the field of immuno-oncology. A potent and selective IDO1 inhibitor such as Epacadostat (EPA) was shown to enhance the antitumor activity by restoring the immune system fitness. As exposure at the site of action and to its specific target are identified as the most important factors for success in drug discovery, the objective of this study was to explore the target exposure and intra-tumor pharmacodynamics effects of EPA drug on the tumor metabolism. To do so, we used both Quantitative Mass Spectrometry Imaging (QMSI) and liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) technologies in order to monitor drug and metabolites distribution and their endogenous quantity in the CT26 mouse tumor model. Target exposure analysis showed that almost 61% of EPA signal (26 μg/g) was concentrated within 38% of the entire tumor surface. Semi quantitative analysis of this region confirmed a positive correlation between IDO1 expression and EPA concentration. In parallel, pharmacodynamics analysis highlighted a response efficacy through Kyn/Trp ratio calculation that was shown decreasing after EPA treatment as noticed in treated CT26 tumors (−82%), plasma (−63%) and blood (−62%) compared to control samples. Finally, 15% and 85% of Kyn signal was found in regions with high and low EPA, respectively. In this study, using QMSI, we went further than only quantifying the metabolites and the drug, by estimating the pharmacological effect efficacy of the drug through a target exposure study handled in different regions of the tumor either expressing IDO1 or Kyn.