Tandem 3: Linking Subtype Specific Metabolic Fingerprint to Hypoxia Signaling in Cancers Characterized by Different Driver Mutations

Short Summary:

We develop molecular imaging assays targeting hypoxia signaling and tumor metabolism in order to identify and characterize tumor subtype specific metabolic profiles. Specifically, we evaluate whether the tumor metabolic profile serves as a prognostic biomarker and if it can be used to monitor tumor progression and therapeutic interventions in a clinical setting.

Scope:

Hypoxia in tumor initiates a sequelae of molecular and ultimately physiological events that are regulated by hypoxia inducible factor (HIF) (Semenza, 2010). Tumor hypoxia is associated with malignancy and resistance to chemo- and radiotherapy. Aside from hypoxia, metabolism has been shown to affect HIF signaling. Mutations of glycolytic enzymes associated with altered activity and correspondingly altered metabolite levels have been identified in many tumor types. Several TCA cycle metabolites have been shown to interact with prolyl hydroxylases thereby affecting HIF activity (DeBerardinis et al., 2008; Semenza, 2010). Current molecular imaging methods targeting HIF are based on reporter genes assays (Lehmann et al., 2009) and cannot be translated into the clinics. The scope of the project is to develop metabolic imaging based assays that can be used as surrogate of HIF activity. Basic research aspects of this project are supported by the SNF as a Synergia project (M.Rudin, W.Krek, H.Moch).

Specific Aims:

The objective of this project is to develop molecular imaging assays targeting hypoxia signaling and tumor metabolism in order to demonstrate metabolic regulation of HIF signaling in vivo in tumor models characterized by different driving mutations of cancer cell lines (e.g. KRAS, BRAF) to identify and characterize tumor subtype specific metabolic profiles. Metabolic enzymes of interest are selected on the basis of human tumor tissue specimen. MR spectroscopic techniques using 13C labeled hyperpolarized substrates will be developed to probe the respective enzyme activity under in vivo conditions and to relate it to HIF signaling assessed in vivo via fluorescent reporter gene based assays. It will be evaluated whether the tumor metabolic profile would serve as a prognostic biomarker. In a second step these tools will be applied to monitor tumor progression and therapeutic interventions in longitudinal studies and to translate the metabolic readouts into the clinics.

Molecular imaging techniques used:

Magnetic Resonance Spectroscopy, Positron Emission Tomography (to assess the level of hypoxia), Fluorescence Molecular Tomography.

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Analysis of tumor samples for mutations (protein levels, metabolite levels)

Added value of KFSP for this specific tandem project:

The expertise gathered in the KFSP will be beneficial for several tandem projects. Relate MR metabolic studies will be carried out in Tandem 5 (cardiovascular metabolic imaging) and Tandem 7 (liver metabolic pathways), which would benefit from sharing both expertise and infrastructure. Similarly the hypoxia signaling assays could be used in projects of Tandem 1 (tumor microenvironment) and Tandem 8 (transplantation of mesenchymal precursor cells).

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