Experimental Anticancer Therapy

The lab focusses on translational research to develop novel treatment options for therapy resistant cancer types including primary brain tumors, melanoma, and pulmonary malignancies. Three main approaches are followed: 1) dissection of molecular factors underlying intrinsic and/or therapy acquired resistance; 2) development of novel tumor-targeted anticancer (metal) compounds preferentially activated within the malignant tissue; 3) identification of novel treatment targets and biomarkers.

Therapy resistance and diagnosis at already disseminated stage are the main causes for cancer death. Additionally, the success of chemotherapy and also of novel “targeted” cancer drugs including immunotherapy is limited by severe side effects and resistance development. Consequently, our lab is involved in translational research projects dealing with the identification of novel therapy targets and tumor-targeting anticancer compounds directed against therapy-resistant solid tumors and/or avoiding severe adverse effects by cancer-specific activation. Within this context, cell as well as xeno- and allograft models resistant against chemotherapeutics but also novel targeted anticancer compounds are established. The molecular changes underlying resistance development are dissected using an integrated systems biology approach including array CGH (Figure 1), next-generation sequencing techniques and gene expression arrays to identify targets for resistance reversal.

Figure 1: Characterisation of therapy resistance mechanisms: KB-3-1 cells with acquired resistance against an experimental metal drug were characterised by array comparative genomic hybridisation (aCGH). An amplified region within chromosome 16p (upper panel) contained the ABCC1 gene coding for a drug efflux pump. The lower panel confirms high level amplification of the ABCC1 gene by fluorescence in situ hybridisation (FISH). Every green dot represents a copy of the ABCC1 gene mainly present on extrachromosomal double minutes.

One of the proteins upregulated during resistance development, namely the major vault protein (MVP), is investigated in more depth regarding a general role in cancer biology. These studies revealed that MVP, as a major constituent of the vault particle, has unexpected roles in the regulation of several cellular processes and signal pathways (MAPK, PTEN, STAT1) but also cellular immunity and tumor cell migration (Figure 2). With regard to targeted anticancer drugs one topic concerns the oncogenic roles of the FGF/FGFR signaling module and its quality as therapeutic target (Figure 3).

Figure2: Vault particles (major vault protein MVP in green) is involved in the migratory function of human glioblastoma cells and accumulates at the ruffling borders and the nuclear membrane.

Figure 3: Subcellular localization of clinically approved FGFR inhibitors. Distinctly different intracellular distribution of the clinically approved FGFR inhibitors ponatinib (blue in the left panel) and nintedanib (green in the right panel) in FGFR driven non-small cell lung cancer cells. In both cases the lysosomes were stained with Lysotracker in red. While ponatinib does not accumulate in the lysosomal compartment, nintedanib strongly does (yellow in the right overlay).

Additionally, a close cooperation exists with the team of Prof. Keppler at the Institute of Inorganic Chemistry within an interuniversity research platform for Translational Cancer Therapy Development. This allows synthesis of novel anticancer compounds and to develop new tumor targeting strategies. Additionally, the platform aims to gain more insights into the mode of action underlying the activity of already established anticancer compounds as well as to enhance the understanding of the mechanisms involved in therapy failure. There are several subprojects within the platform such as preclinical development of new metal drug derivatives, thiosemicarbazone-based compounds, tyrosine kinase inhibitor prodrugs, and immunogenic cell death-inducing (metal) drugs for immunotherapy. One of the lead compounds developed within the platform (the ruthenium complex KP1339) is currently tested with promising results in a clinical phase I/II trial.