Medical University of Vienna
Institute for Cancer Research (Deputy Head)
Department of Medicine I
1090 Vienna, Austria
Phone: +43 1 40160-57502
Fax: +43 1 40160-957502
Our laboratory focusses on the molecular characterization of innovative cancer therapy targets and respective therapy resistance mechanisms in order to develop novel treatment strategies, synergistic combination regimens and targeted anticancer compounds. In close collaboration of clinical departments (oncology, pathology, surgery, pharmacology), our trasnlational research projects are mainly targeting notoriously therapy resistant cancer types including pediatric and adult brain tumors and thoracic malignancies.
Role of subcellular trapping and altered lipid metabolism in resistance against tyrosine kinase inhibitors. In the past years we have generated several in vitro and in vivo models of FGFR-driven lung cancer1,2 and mesothelioma3–5 to elucidate clinically relevant resistance mechanisms against TKIs67. Recently, we found that resistance to ponatinib is accompanied by the accumulation of ponatinib in intracellular lipid droplets (LD), and the sensitivity of cells restored by decreasing LD levels. Based on these results, we hypothesize that LD sequestration is a yet unknown mechanism involved in intrinsic and acquired resistance to ponatinib and, possibly, other lipophilic anticancer drugs including TKIs. The thesis project will dissect the impact of FGFR inhibitors on the lipid metabolism and LD formation of cancer cells and 3D-spheroids, using lipidomics/metabolomics8 in combination with RNAseq (cooperation with G. Köllensperger, UniVien). Conversely, the relevance of altered lipid metabolism on ponatinib response will be evaluated by pharmacological intervention (using FAS, SOAT-1 and mevalonate pathway inhibitors) or CRISPR-Cas9 (targeting microsomal triglyceride transfer, which is significantly overexpressed after ponatinib selection) in FGFR-driven lung cancer and BCR-ABL-driven CML models in vitro and in vivo. Co-culture experiments with adipocytes will clarify whether preferential sequestration into adipose cells may contribute to ponatinib resistance. The derivatization of ponatinib is currently underway to identify molecular structures responsible for LD sequestration (with B. Keppler, UniVien). The potential of the new analogs to overcome ponatinib resistance will be assayed.
- Preusser, M.; Berghoff, A. S.; Berger, W.; Ilhan-Mutlu, A.; Dinhof, C.; Widhalm, G.; Dieckmann, K.; Wöhrer, A.; Hackl, M.; von Deimling, A.; et al. High Rate of FGFR1 Amplifications in Brain Metastases of Squamous and Non-Squamous Lung Cancer. Lung Cancer Amst. Neth. 2014, 83 (1), 83–89. doi.org/10.1016/j.lungcan.2013.10.004.
- Fischer, H.; Taylor, N.; Allerstorfer, S.; Grusch, M.; Sonvilla, G.; Holzmann, K.; Setinek, U.; Elbling, L.; Cantonati, H.; Grasl-Kraupp, B.; et al. Fibroblast Growth Factor Receptor-Mediated Signals Contribute to the Malignant Phenotype of Non-Small Cell Lung Cancer Cells: Therapeutic Implications and Synergism with Epidermal Growth Factor Receptor Inhibition. Mol. Cancer Ther. 2008, 7 (10), 3408–3419. doi.org/10.1158/1535-7163.MCT-08-0444.
- Schelch, K.; Hoda, M. A.; Klikovits, T.; Münzker, J.; Ghanim, B.; Wagner, C.; Garay, T.; Laszlo, V.; Setinek, U.; Dome, B.; et al. Fibroblast Growth Factor Receptor Inhibition Is Active against Mesothelioma and Synergizes with Radio- and Chemotherapy. Am. J. Respir. Crit. Care Med. 2014, 190 (7), 763–772. doi.org/10.1164/rccm.201404-0658OC.
- Schelch, K.; Wagner, C.; Hager, S.; Pirker, C.; Siess, K.; Lang, E.; Lin, R.; Kirschner, M. B.; Mohr, T.; Brcic, L.; et al. FGF2 and EGF Induce Epithelial-Mesenchymal Transition in Malignant Pleural Mesothelioma Cells via a MAPKinase/MMP1 Signal. Carcinogenesis 2018, 39 (4), 534–545. doi.org/10.1093/carcin/bgy018.
- Laszlo, V.; Valko, Z.; Kovacs, I.; Ozsvar, J.; Hoda, M. A.; Klikovits, T.; Lakatos, D.; Czirók, A.; Garay, T.; Stiglbauer, A.; et al. Nintedanib Is Active in Malignant Pleural Mesothelioma Cell Models and Inhibits Angiogenesis and Tumor Growth in Vivo. Clin. Cancer Res. 2018, clincanres.1507.2017. doi.org/10.1158/1078-0432.CCR-17-1507.
- Englinger, B.; Lötsch, D.; Pirker, C.; Mohr, T.; Schoonhoven, S. van; Boidol, B.; Lardeau, C.-H.; Spitzwieser, M.; Szabó, P.; Heffeter, P.; et al. Acquired Nintedanib Resistance in FGFR1-Driven Small Cell Lung Cancer: Role of Endothelin-A Receptor-Activated ABCB1 Expression. Oncotarget 2016, 5 (0).
- Englinger, B.; Kallus, S.; Senkiv, J.; Heilos, D.; Gabler, L.; van Schoonhoven, S.; Terenzi, A.; Moser, P.; Pirker, C.; Timelthaler, G.; et al. Intrinsic Fluorescence of the Clinically Approved Multikinase Inhibitor Nintedanib Reveals Lysosomal Sequestration as Resistance Mechanism in FGFR-Driven Lung Cancer. J. Exp. Clin. Cancer Res. CR 2017, 36 (1), 122. doi.org/10.1186/s13046-017-0592-3.
- Schwaiger, M.; Rampler, E.; Hermann, G.; Miklos, W.; Berger, W.; Koellensperger, G. Anion-Exchange Chromatography Coupled to High-Resolution Mass Spectrometry: A Powerful Tool for Merging Targeted and Non-targeted Metabolomics pubs.acs.org/doi/abs/10.1021/acs.analchem.7b01624 (accessed May 4, 2018). doi.org/10.1021/acs.analchem.7b01624.