Uncovering Metabolic Pathways in Disease to Support Drug Discovery Using High Resolution MALDI Imaging Mass Spectrometry

June 16, 2016

8:00 a.m. PDT / 11:00 a.m. EDT / 16:00 BST / 17:00 CEST

Overview

Matrix assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) is a robust, label free tool to produce ion-density maps representing the distribution of a variety of analytes within a tissue section of interest. Incorporation of high-resolution FTICR (Fourier transform ion cyclotron resonance) mass spectrometers into existing workflows has now allowed for simultaneous detection of drug and downstream pharmacodynamic responses in a single acquisition.

This approach was recently utilized to assess the effects of a drug compound known to elicit a PD response targeting the tryptophan pathway. Whole body tissue sections derived from tumor bearing mice dosed with drug or vehicle were analyzed using MALDI FTICR IMS to evaluate the tissue distribution of tryptophan metabolites. Tissues were sectioned and analyzed in positive ion mode, where 21/24 of the nodes of the pathway could be identified Two central nodes of the tryptophan metabolism pathway, tryptophan and kynurenine were found to have a pharmacodynamic response to dosing, with tryptophan increasing and kynurenine decreasing in tumors, a finding validated not only by MALDI-IMS but also a complimentary quantitative LC-MS/MS assay.

Following the success of the tryptophan study, method development to image additional key metabolic pathways, such as the TCA cycle are ongoing. Preliminary data from these efforts will be presented, along with 3D images representing the first feasibility study to confirm that 3D volume reconstruction is achievable using data collected on an FTICR mass spectrometer. The 3D imaging study was made possible using new acquisition software from Bruker Daltonics and 3D reconstruction software from SCiLS version 2015a (Bremen, Germany). A variety of lipid species including phosphatidylcholines and sphingomyelins were identified across a 3D volume

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