Metal complexes targeting tumour metastasis and vascularisation on a cellular and molecular level

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Over 90% of the eight million cancer dead every year died of metastases. While the therapy of primary tumours has made great progress, the clinical control of metastasis is limited to a mere screening of potential target organs and tumour markers. There is no dedicated anti-metastatic drug on the market. This project aims to develop drugs that specifically address proteins which play crucial roles in the various stages of the metastasis process, e.g. the invasion of neighbouring tissues by cancer cells and the vascularisation of developing microtumours. Structurewise, the focus is on complexes of late transition metals with chelate and carbene ligands derived from inherently bioactive natural products. These complexes offer many ways of fine-tuning their affinity for and impact on target proteins by modifying their organic ligands and by exploiting the redox properties, coordination modes and geometries of their central metal fragments.In the second funding period we will refine complex motifs that had previously been identified as inhibitors of prometastatic proteins, e.g. metallocenyl–sphingoid complexes which inhibit ceramidase. In addition, we will also devise new complexes bearing ligands derived from established cancer drugs with weakly antimetastatic side effects in order to potentiate the latter and overcome the pharmacological shortcomings of the parent drug. We will explore this strategy for the development of inhibitors of the angiogenic and prometastatic hypoxia-inducible factor, and for complex derivatives of the antimetabolite fludarabine, a clinical mainstay of cancer therapy.The efficacy of new complexes will be evaluated in vitro and also in vivo on developing microtumours implanted in the chorioallantoic membrane of fertilised chicken eggs and in zebrafish. Tests on stem-cell-like circulating epithelial cancer cells of actual tumour patients will allow to earmark the most appropriate drug for a future metastasis.