KFO 262:  Tumour Metabolism as Modulator of Immune Response and Tumour Progression

• Subject Area: Medicine
• Term: from 2011 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190230491

The Clinical Research Unit aims at analysing the altered metabolism of tumour cells and its impact on the body¿s immune system to identify specific therapeutic targets in metabolic pathways for the inhibition of tumour growth and reactivation of the immune system.
Two of the seven funded projects investigate the role of increased glucose and glutamine metabolism in tumour and the resultant increased production and secretion of lactic acid. The aim is not only to elucidate how lactic acid inhibits the activity and infiltration of immune cells in tumours, but also to test novel therapeutic approaches to inhibiting the production of lactic acid in vitro and in vivo. Further, the impact of lactic acid on the secretion of protumourigenic factors and the regulation of natural killer cells by hepatic stellate cells will be investigated.
Another metabolite of interest is 5'-methylthioadenosine (MTA), an intermediate of the methionine and polyamine metabolism. Its concentration is increased in many tumours due to a deficiency of 5'-methylthioadenosine phosphorylase (MTAP). Increased levels of MTA do not only inhibit the response to interferons, but also stimulate migration of cancer cells and suppress T-lymphocyte activity. Primary goals are to reduce the metastatic potential of cancer cells and to restore tumour specific T-cell function for an improved efficacy of cellular immune therapeutic approaches by administering small molecule inhibitors of the MTAP/MTA signalling pathway.
Another project focusses on the heat shock protein Hsp90, which plays an essential role in stabilising proteins that regulate tumour metabolism and angiogenesis. The pharmacologic inhibition of Hsp90 represents a promising approach in tumour therapy and the planned studies on the impact of Hsp90 inhibitors on tumour metabolism will lay the foundation for their clinical application in the treatment of gastrointestinal and hepatic cancers.
The remaining two projects will develop and apply sensitive analytical methods for the accurate determination of metabolite abundance and flux in cells and tissues as well as peptides and proteins that mediate tumour progression and immune escape as a result of tumour specific alterations in cell metabolism.

• DFG Programme: Clinical Research Units

Projects

• Cental project (Applicant Kreutz, Marina P. )
• Characterization of UVA induced metabolic changes in melanoma in vitro and in vivo and identification of therapeutic targets (Applicants Berneburg, Mark-Jürgen ;  Kamenisch, York )
• Development and application of analytical methods for metabolic cell analysis under patho-physiological conditions (Applicants Dettmer-Wilde, Katja ;  Gronwald, Wolfram ;  Oefner, Peter ;  Spang, Rainer )
• Differentiation and activation of immune cells in the tumor microenvironment: role of tumor-derived lactate in immunomodulation in vitro and in vivo (Applicants Kohl, Elisabeth ;  Kreutz, Marina P. ;  Köhl, Gudrun )
• Heat-shock protein 90 (Hsp90) blockade as a therapeutic approach for modulating tumor metabolism and angiogenesis in cancer (Applicant Lang, Sven Arke )
• IDH mutations in the interplay of metabolism and antileikemic immune response (Applicants Herr, Wolfgang ;  Kreutz, Marina P. ;  Thomas, Simone )
• Impact of drugs targeting tumor metabolism on human CD8 T cell effector functions (Applicants Herr, Wolfgang ;  Renner-Sattler, Kathrin )
• Metmorfin as adjuvant therapy for glioblastoma - a pathway to clinical phase I/II-trials (Applicants Leitzmann, Michael ;  Seliger, Corinna )
• Proteomics and functional analysis of glucocorticoid-induced apoptosis of lymphoblastic leukemia cells under simultaneous administration of 2-deoxy-D-glucose (Applicant Oefner, Peter )
• Regulation and role of GLUT1 in hepatocellular carcinoma with focus on the interaction between tumor and activated hepatic stellate cells (Applicant Hellerbrand, Claus )
• Role of 5'-methylthioadenosine in tumor progression (Applicant Bosserhoff, Anja-Katrin )
• Suppression of human T cells by 5'-methylthioadenosine (Applicants Aigner, Michael ;  Mackensen, Andreas )

• Spokesperson: Professor Dr. Peter Oefner
• Leader: Professorin Dr. Marina P. Kreutz