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

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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.