SLAS Discovery - Special Issue on Advances in MALDI Mass Spectrometry for Drug Discovery - Volume 22 Issue 10 - December 2017 - 1189

Ait-Belkacem et al.

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Figure 5. Tumor metabolic interactions with the microenvironment highlighted by matrix-assisted laser desorption/ionization
mass spectrometry imaging. IDO1-mediated Trp degradation results in inhibition of T-cell effector proliferation, apoptosis, de novo
hyperactivation of T-reg, generation of tolerogenic dendritic cells, and promotion of M2-macrophages. Cancer cells alter the chemical
composition of the extracellular medium, which exerts pleiotropic effects on the phenotypes of normal cells that reside in the vicinity
of the tumor as well as the extracellular matrix. Reciprocally, the microenvironment affects the metabolism and signaling responses of
cancer cells themselves.

acute myeloid leukemia, in which the serum kynurenine/
tryptophan ratio (Kyn/Trp) was raised. This analysis allowed
for the detection of a higher IDO1 activity than in healthy
people, suggesting that patients with higher Kyn/Trp ratios
showed lower survival.22 Serum concentrations of Kyn have
also been reported to predict overall survival in diffuse large
cell lymphoma23 and to correlate with treatment response in
adult T-cell leukemia/lymphoma.24 Moreover, measuring
kynurenine, tryptophan, and downstream metabolites in
patients' sera has been assessed in a cohort of myelodysplastic syndrome patients.25 More recently, the first-in-human
phase 1 study investigating the maximum tolerated dose,
safety, pharmacokinetics, pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent and
selective inhibitor of IDO1, followed kynurenine/tryptophan
ratio by LC-MS/MS analysis.26 Thus, Trp catabolism can be
easily monitored in patient sera and may have predictive
value. However, biomarker histological localization is still
of high importance given the correlation between the

immune infiltrate and the metabolite signature (beyond the
Kyn/Trp quantitation). Regarding this high tumor heterogeneity, many notable applications in cancer research are
effectively based on the determination of marker levels. This
could characterize a patient population with a better likelihood to respond to some treatments, such as the expression
of human epidermal growth factor receptor 2 (HER2) for
trastuzumab (Herceptin) therapy. HER2 has been considered
since 2006 as a biomarker in patients diagnosed with invasive breast cancer.27 In this specific example, the two tests
for HER2 status, IHC and fluorescence in situ hybridization,
rely on a highly subjective manual interpretation step. By
employing MALDI MSI, Walch and colleagues28 constructed a model for the classification of breast tumor HER2
status with a sensitivity of 83% and specificity of 92%. For
this purpose, MALDI MSI is considered as a very promising
ex vivo tool to investigate, using molecular lenses, histological biomarkers of diagnosis, prognosis, and response to
treatments.29
Table of Contents for the Digital Edition of SLAS Discovery - Special Issue on Advances in MALDI Mass Spectrometry for Drug Discovery - Volume 22 Issue 10 - December 2017
