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SP1 - Modeling of metabolic changes in human IDHmut and IDHwt gliomas.

Tryptophan (Trp) is converted into a plethora of metabolites, including well known compounds such as serotonin and melatonin but also kynurenine and NAD. Several metabolites of the Kyn pathway (e.g. the NMDA agonist QA and the antagonist KynA) have neuroactive or signaling function, highlighting the pathophysiological importance of Trp-Kyn-NAD metabolism. In malignant gliomas the Trp pathway plays an important role in promoting malignancy. As part of a collaborative systems medicine effort to establish a network model in malignant glioma, we will focus on integrating experimental data of our partners into theoretical models. We will use this as well as existing expression data to analyze glioma subtype specific changes in metabolism in general and changes in Trp and NAD metabolism in particular. We will furthermore look into particular aspects of metabolite competitions for enzymatic binding sites with an emphasis on how metabolite concentrations are influenced under pathophysiological conditions. The results achieved in this project will allow us to study individual network components as well as their concerted influences on each other. These insights will help us to identify therapeutic targets and their combinations for the treatment of malignant glioma.

SP2 - Experimental analysis of Trp and NAD metabolism in human gliomas and integration of the experimental and modeling results of the consortium with clinical data

The central aims of subproject 2 are two-fold: i) experimental analysis of Trp and NAD metabolism and ii) integration of the experimental and modeling results of the consortium with clinical data.
Two clinically relevant metabolic pathways in glioma are Trp and NAD metabolism. In subproject 2 expression analyses of the enzymes involved in Trp and NAD metabolism as well as corresponding targeted metabolic measurements will be performed in IDH mutant and wild type glioma cells and tissues WHO°II-IV. The results of these measurements will be employed to validate and refine the model of Trp and NAD metabolism developed in subproject 1. In addition, the obtained results will be used to extract metabolic markers for the activity of specific metabolic routes in IDH mutant or wild type gliomas. Ultimately, these markers will allow stratification of glioma patients to treatments and the assessment of treatment efficacy.
The second aim of subproject 2 is to integrate our experimental and modeling results with clinical data. Public data covering low grade gliomas as well as glioblastoma will be analyzed using the model of Trp and NAD metabolism developed in subproject 1 and the AHR signature developed in subproject 3. The results of these analyses will be integrated with the available clinical data regarding 1) characteristics of the tumor such as histological type, grade and location, 2) characteristics of the patients such as age, gender and ethnicity, 3) association with symptomatic seizures or other comorbidities 4) association with treatments such as preoperative corticosteroids, anti-seizure medication or radiation therapy and 5) overall survival.

SP3 - The role of AHR activation on metabolism and methylation in IDHmut and IDHwt human gliomas.

The ligand-activated aryl hydrocarbon receptor (AHR) is known predominantly for its role in mediating toxic effects of chemicals. However AHR is also involved in (patho-) physiological processes and can be activated by endogenous compounds, for example by tryptophan metabolites (Trp). AHR signaling is therefore closely linked with Trp metabolsm, which is known to promote the aggressiveness of human gliomas. As part of a joint Systems Medicine project to establish a network model in malignant glioma we will specifically elucidate the role of AHR in this context. Consequences of AHR activation will be evaluated on the DNA-, gene-, and protein-level in IDH mutant and wildtype glioma cells. In addition, publically available gene expression and DNA binding studies will be used to establish a glioma-specific AHR activation signature to assess the role of AHR signaling in human glioma tissue. The results achieved in this project will be incorporated into our network model and used for optimization.

SP4 - mTOR interactions with metabolic networks in malignant glioma: an integrative experimental-computational approach

Mammalian target of rapamycin (mTOR) network genes are altered in malignant gliomas, and mTOR inhibitors are in clinical studies for the treatment of gliomas. mTOR kinase contributes to cancer cell survival, growth, and motility via several signaling and metabolic routes. However, the relative contribution of these routes to glioma progression and the impact of differing mTOR network activities for drug responsiveness remains poorly explored. The main aim of subproject 4 is to analyze mTOR signaling in malignant glioma. In a combined modeling-experimental approach we will analyze the effects for single and combinatorial drug treatments targeting the mTOR network in glioma cells. Thus, our approach will identify drugs and combinations thereof which specifically limit IDHWT or IDHmut glioma cell growth.

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