The degeneration of healthy somatic cells into malignant cancer cells is closely connected to epigenetic changes in the cells‘ genome. This includes the hypermethylation of so-called tumor suppressor genes through enzymes which are referred to as DNA methyltransferases (DNMT). Unlike genetic mutations, this type of change, however, can, in principle, be reversed and therefore presents a promising approach to the development of new drugs.
The project therefore looks at the design, synthesis and the pharmaceutical development of so-called DNA methyltransferase inhibitors, which intervene in the metabolism of cells and are intended to specifically prevent the hypermethylation of tumor suppressor genes. Besides a specially developed animal model and modern imaging processes, cancer stem cells (CSC) are also used as part of the development.
Cancer stem cells are regarded as germ cells for the formation and growth of tumors. They are equipped with the characteristics typical of stem cells, such as the ability to self-regenerate, or a high differentiation potential. Recent studies allow the assumption that the CSC are particularly resistant to common types of therapy (chemotherapy, radiotherapy) and are therefore responsible for relapses and metastasis. The development of therapy concepts which specifically aim to eliminate CSC is therefore of utmost urgency. The cancer stem cell lines established at the Fraunhofer IZI thus represent an ideal platform for pharmacological development.
As part of the project, the DNMT-relevant target molecules within the CSC-specific signaling pathways are first to be identified and characterized. The DNMT inhibitors identified as being optimal will then be evaluated in a GLP trial on the basis of selected CSC compartments in the animal model. The tumor initiation derived from CSC and the DNMT-based remission of a malignancy can thereby be monitored using bioluminescence imaging. At the same time, the modern imaging procedure allows the entire progress of the disease and therapy within the organism to be observed.