Novel Anticancer Agents – from Design to Clinical Translation

However, especially immunotherapy in advanced but also earlier cancer stages and (neo)adjuvant treatment settings is only delivering its full potential within combination regimens often containing platinum-based chemotherapy. Nonetheless, the chemotherapeutic arm of this success story has remained widely unchanged during the last decades, and – due to severe adverse effects and the rapid emergence of resistance mechanism – metal-based chemotherapies are in urgent need for optimization.

Consequently, the key aim of the cluster project is to develop smart metal (pro)drugs – based on platinum, ruthenium, gallium, tungsten, molybdenum – with novel and tumor-specific modes-of-action. This will yield, besides the cytotoxic anticancer effects, immune-stimulatory and other bioactive functions. The developed compounds are designed to introduce precision medical approaches into the field of anti-cancer metal therapy.

Concerning translation towards clinical use, the compounds derived from this cooperation cover a wide range of preclinical and clinical development stages. Novel prodrug systems activated specifically in the malignant tissue are currently being synthesized or have already been successfully tested in vivo. Two compounds developed within the cluster project (a ruthenium and a gallium complex), are currently undergoing phase II clinical evaluation, having shown promising activity in the respective clinical phase I studies. Key novel technologies (e.g. CRISPR-based screenings for activity and resistance mechanisms) and model systems (humanized mice, tumor spheroids and organoids), combined with access to clinical material from clinical studies allow to dissect in detail the mode-of-action and resistance of the developed compounds and to optimize strategies for their translation towards clinical application.

Since the establishment of the research platform “Translational Cancer Therapy Research” in 2009 as a joint project of Bernhard Keppler from the Institute of Inorganic Chemistry of the University of Vienna and Walter Berger from the Institute of Cancer Research of the Medial University of Vienna, the two research institutions have developed a close and integrative cooperation between synthetic and analytical chemistry as well as biological and pharmacological knowhow. This interdisciplinary cluster project thus constitutes an optimal basis for translational approaches connecting high-end basic research derived from both cooperating universities with the chance for clinical evaluation and, ultimately, patient benefit.