Targeted and untargeted metabolomics in IDH1 mutated xenografts in mice

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Here, we will run a comprehensive global analysis of metabolic changes in established cell lines and most importantly in tissue samples where the microenvironment best mimics the human tumors. We are also expanding on our discovery that the S1P-to-ceramide rheostat in IDH1mut glioma is already skewed toward apoptosis12. Because this balance is important in dictating whether apoptosis or cellular proliferation occurs, we aim to modulate S1P-to-ceramide distribution to induce cell death. We are achieving this goal by using the following two approaches: First, we are exploring a combinatorial approach consisting in inhibiting sphingosine kinase 1 (SPHK1) with N,N dimethyl sphingosine (NDMS)-the only expressed enzyme of S1P formation in these tumors, -while also adding sphingosine-C17 (SphC17). We demonstrated that such inhibition is specific to IDH1mut glioma12,20. Treating two IDH1mut oligodendroglioma cell lines with the combination of NDMS and SphC17 showed increased expression of markers for apoptosis (cleaved PARP1)20. Surprisingly, in the treated samples, we found decreased synthesis and import of cholesterol, suggesting a previously uncharacterized and potentially important link between altered sphingolipid metabolism and cholesterol homeostasis. To determine the efficacy of this drug combination in vivo, we plan to use oligodendroglioma cell lines and mouse models acquired via collaborations. In the second approach to modulating the S1P-to-ceramide rheostat toward cell death, we will increase the levels of ceramides by independently inhibiting acid ceramidase, the lysosomal enzyme that converts ceramide into sphingosine and releases fatty acids. We have already shown that this inhibition increases ceramide levels up to 30-fold and induces cell death.