Frezza, Christian | Schatton, Désirée - A 02

Heterozygous germline mutations of the Tricarboxylic Acid (TCA) cycle gene Fumarate Hydratase (FH) predispose individuals to hereditary leiomyomatosis and renal cell carcinoma (HLRCC). This cancer syndrome is characterised by benign tumours of the skin and uterus, as well as an aggressive form of renal cancer that metastasises even when small. Treatment options for this cancer type are limited and have poor efficacy, leading to an abysmal prognosis for affected patients. Therefore, developing preventive interventions for HLRCC family members and novel anticancer strategies is crucial for improving the clinical outcomes of these patients. 

We have demonstrated that the loss of FH creates unique metabolic vulnerabilities and that depleting specific nutrients can selectively kill FH-deficient cancer cells. However, this work was primarily conducted in cultured cell lines, and validation in vivo has been inadequate. In this proposal, we will explore the effects of dietary interventions aimed at addressing the specific metabolic needs of FH-deficient cells as preventive and therapeutic strategies in a novel HLRCC mouse model, utilising state-of-the-art metabolomics techniques combined with in vitro and in vivo biochemical assays.

This study will provide a comprehensive time-resolved characterisation of metabolite trajectories, as well as the onset of disease and survival in animal models of HLRCC. In addition to elucidating novel disease mechanisms implicated in HLRCC, this work will identify dietary interventions that can be employed for tumour prevention and therapy.

• Characterization of tamoxifen inducible Fh1-deficient mouse models
• Dietary interventions
• State-of-the-art metabolomics techniques

For more information, please check Professor Frezza´s Lab Website.

• University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute for Metabolomics in Ageing, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), Cologne, Germany
• University of Cologne, Faculty of Mathematics and Natural Sciences, Institute of Genetics, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), Cologne, Germany
• University of Cologne, Center for Molecular Medicine (CMMC), Cologne, Germany

• University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute for Metabolomics in Ageing, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), Cologne, Germany
• University of Cologne, Center for Molecular Medicine (CMMC), Cologne, Germany