Preclinical Evaluation of New Anticancer Metal Compounds

Metal compounds have a central position in successful treatment of diverse human cancers today. The clinical applicability is, however, limited by intrinsic and/or acquired drug resistance. Consequently, it is of utmost importance for the successful preclinical development of new anticancer agents to clarify on the one hand the molecular basis of their anticancer activity and on the other hand the impact of cellular resistance mechanisms. These preclinical investigations should support the planning of clinical studies based on the selection of appropriate tumor types and patient collectives. In this respect, such data are of central importance for combating cancer more efficiently. From the economical point of view, the gained knowledge is essential for the avoidance of costly but unsuccessful clinical studies and, as a consequence, termination of the development of potentially successful anticancer drugs. For roughly a decade our research group at the Institute of Cancer Research, Department of Medicine I, Vienna, (directed by Prof. Dr. Micksche), has its major focus on therapy and therapy resistance mechanisms in solid tumors. About a year ago a fruitful cooperation was started with the Institute of Inorganic Chemistry; Vienna University (directed by Prof. DDr. Keppler) specialized on the synthesis of tumor-targeted, anticancer metal complexes. Aim of the cooperation is to support preclinical evaluation of these promising antineoplastic agents. Studies started by investigating a ruthenium and a gallium complex which recently gave promising results in clinical phase I trials. While the clinical trials are financed by Faustus Forschung Austria Translational Drug Development AG, Vienna, preclinical studies can not be adequately supported by this small company. Thus, the presented proposal aims on the preclinical investigation of several types of metal complexes, all exerting promising cytostatic activity and selected as lead compounds. The investigations will include several metal drugs (ruthenium, gallium, cerium, lanthanum, platinum complexes) developed by Faustus, as well as experimental metal drugs from other sources (e.g. NAMI-A), and for comparison the already clinically used platinum compounds cisplatin, carboplatin, and oxaliplatin. Our scientific approach aims to clarify the molecular basis of anticancer activities as well as the impact of intrinsic and acquired drug resistance mechanism. Moreover, the study should give information which tumor types are likely to respond to the investigated drugs and which marker proteins allow to predict sensitivity/resistance. In summary the generated data should contribute to the successful development of the investigated drugs and, hopefully, to improved treatment of cancer.