The development of metal-based anticancer agents in the 1970s was a milestone in cancer treatment. Despite their unique efficacy, only a handful of agents of this class have been approved to date, including primarily platinum-containing compounds such as cisplatin, carboplatin and oxaliplatin, but also arsenic trioxide. The ruthenium-based drug candidate BOLD-100, originally developed as KP1019 (KP1339) by chemist and physician Bernhard Keppler, Head of the Department of Inorganic Chemistry at the University of Vienna, showed promising efficacy and tolerability in clinical trials conducted so far. Among others, first positive results have been shown in neuroendocrine (hormone-producing) tumours. BOLD-100 is a small molecule that which is transported into the tumour cell via the protein albumin and selectively activated there, resulting in the death of the cancer cells. Multi-omics: Combined data analysis offers new insights "In preclinical studies, BOLD-100 had excellent tumour-inhibiting effects in cancer types that weakly respond to platinum-based agents. We also know that the drug candidate creates stress in the endoplasmic reticulum, which constitutes a subunit of the cell that regulates lipid anabolism and protein maturation. However, there was a lack of understanding about the detailed mode of action of the active agent, especially with regard to potential target molecules to which the compound can bind and thus trigger the observable anticancer effects," say study authors Samuel Meier-Menches and Christopher Gerner from the Department of Analytical Chemistry. In cooperation with researchers from the Medical University of Vienna, they investigated in detail the molecular mode of action of BOLD-100. Based on a multi-omics approach (a combined data analysis of the proteome and gene expressions), the researchers showed that BOLD-100 disturbs ribosomal constituents in the cancer cells, resulting in stress in the endoplasmic reticulum. "We were also able to identify potential protein binding partners of BOLD-100, more specifically the ribosomal proteins RPL10 und RPL24. Imaging techniques confirmed our results," says first author Benjamin Neuditschko from the Faculty of Chemistry, University of Vienna. Bridging pre-clinical and clinical research "A comprehensive understanding how these active agents work enables us to use them in a targeted manner," the researchers conclude in their study that now has been published as cover story of "Angewandte Chemie". Post-genomic approaches to investigate modes of action are one of the main goals of the Joint Metabolome Facility, a joint research platform of the University of Vienna and the Medical University of Vienna. The discovery and further development of metal-based agents for tumour types that were previously untreatable or difficult to treat are a main focus of the research cluster Translational Cancer Therapy Research, led by Bernhard Keppler (Faculty of Chemistry, University of Vienna) and Walter Berger (Medical University of Vienna). Source
