The tumor microenvironment as target and regulator of anticancer (metal) drug response

Research interests

The research group focusses on a translation of basic research data towards clinical application to foster the understanding of cancer therapy responses and the causes of intrinsic and acquired therapy resistance. Moreover, we develop systemic cancer therapy with a focus on notoriously therapy resistant cancers including primary brain tumors, thoracic malignancies and sarcomas.

1. Identification of novel therapeutic molecular targets and the respective inhibitors
2. Development of tumor-targeted small molecule anticancer agents and smart metal drugs with tumor-specific activity and reduced adverse effects (in cooperation with the Institute of Inorganic Chemistry and the research cluster “Translational Cancer Therapy Research” (https://tctr.univie.ac.at/)
3. Dissection of drug resistance mechanisms and development of circumvention approaches partly in course of the International PhD School Translational Oncology (IPPTO, https://phd-ippto.meduniwien.ac.at/)

Selected publications

1. Pirker C, Bilecz A, Grusch M, Mohr T, Heidenreich B, Laszlo V, Stockhammer P, Lötsch-Gojo D, Gojo J, Gabler L, Spiegl-Kreinecker S, Doeme B, Steindl A, Klikovits T, Hoda MA, Jakopovic M, Samarzija M, Mohorcic K, Kern I, Kiesel B, Brcic L, Oberndorfer F, Müllauer L, Klepetko W, Schmidt WM, Kumar R, Hegedus B, Berger W. Telomerase reverse transcriptase promoter mutations identify a genomically defined and highly aggressive human pleural mesothelioma subgroup. Clin Cancer Res. 2020; 26(14):3819-3830. doi: 10.1158/1078-0432.CCR-19-3573.
2. Englinger B, Laemmerer A, Moser P, Kallus S, Röhrl C, Pirker C, Baier D, Mohr T, Niederstaetter L, Meier-Menches SM, Gerner C, Gabler L, Gojo J, Timelthaler G, Senkiv J, Jäger W, Kowol CR, Heffeter P, Berger W. Lipid droplet-mediated scavenging as novel intrinsic and adaptive resistance factor against the multikinase inhibitor ponatinib. Int J Cancer. 2020 Sep 15;147(6):1680-1693. doi: 10.1002/ijc.32924.
3. Guarra F, Terenzi A, Pirker C, Passannante R, Baier D, Zangrando E, Gómez-Vallejo V, Biver T, Gabbiani C, Berger W (corr. author), Llop J, Salassa L. ¹²⁴ I Radiolabeling of a Au^III -NHC Complex for in vivo biodistribution studies. Angew Chem Int Ed Engl. 2020 Jul 7. doi: 10.1002/anie.202008046.
4. Gojo J, Englinger B, Jiang L, Hübner JM, Shaw ML, Hack OA, Madlener S, Kirchhofer D, Liu I, Pyrdol J, Hovestadt V, Mazzola E, Mathewson ND, Trissal M, Lötsch D, Dorfer C, Haberler C, Halfmann A, Mayr L, Peyrl A, Geyeregger R, Schwalm B, Mauermann M, Pajtler KW, Milde T, Shore ME, Geduldig JE, Pelton K, Czech T, Ashenberg O, Wucherpfennig KW, Rozenblatt-Rosen O, Alexandrescu S, Ligon KL, Pfister SM, Regev A, Slavc I, Berger W, Suvà ML, Kool M, Filbin MG. Single-cell RNA-seq of pediatric ependymoma reveals prognostic impact of impaired neuronal-glial fate specification. Cancer Cell. 2020 Jul 13;38(1):44-59.e9. doi: 10.1016/j.ccell.2020.06.004.
5. Domarco O, Kieler C, Pirker C, Dinhof C, Englinger B, Reisecker JM, Timelthaler G, García MD, Peinador C, Keppler BK, Berger W (corr author), Terenzi A. Subcellular duplex DNA and G-quadruplex interaction profiling of a hexagonal Pt(II) metallacycle. Angew Chem Int Ed Engl. 2019 Jun 11;58(24):8007-8012. doi: 10.1002/anie.201900934.
6. Englinger B, Pirker C, Heffeter P, Terenzi A, Kowol CR, Keppler BK, Berger W. Metal Drugs and the Anticancer Immune Response. Chem Rev. 2019 Jan 23;119(2):1519-1624. doi: 10.1021/acs.chemrev. 8b00396.

FG3 Team

Research interests

Chemotherapy and therapy with small targeted molecules are two major strategies for therapy of human cancer at the disseminated stage. During the last decades, thousands of compounds have been developed and consequently have improved therapy effectiveness. However, even when using new targeted therapeutics, such therapy is often limited by strong side effects, resistance development and insufficient tumor accumulation.

We focus on the development of several new strategies to overcome these limitations:

1. Improvement of anticancer activity by smart drug combinations;
2. Development of new targeting strategies to increase drug delivery to the tumor tissue (in cooperation with the Institute of Inorganic Chemistry and the research cluster “Translational Cancer Therapy Research” (https://tctr.univie.ac.at/)
3. Investigation on the mechanisms underlying the sensitivity/resistance of cancer cells against new anticancer drugs to define the patient collective which will profit most from chemotherapy in course of the International PhD School Translational Oncology (IPPTO, https://phd-ippto.meduniwien.ac.at/ ).

Selected publications

1. Hager S, Pape VFS, Pósa V, Montsch B, Uhlik L, Szakács G, Tóth S, Jabronka N, Keppler BK, Kowol CR, Enyedy EA, Heffeter P. High copper complex stability and slow reduction kinetics as key parameters for improved activity, paraptosis induction and impact on drug-resistant cells of anticancer thiosemicarbazones. Antioxid Redox Signal. 2020 April 25; doi: 10.1089/ars.2019.7854.
2. Karmakar S, Poetsch I, Kowol CR, Heffeter P (Corr author), Gibson D. Synthesis and Cytotoxicity of Water-Soluble Dual- and Triple-Action Satraplatin Derivatives: Replacement of Equatorial Chlorides of Satraplatin by Acetates. Inorg Chem. 2019 Dec 16;58(24):16676-16688. doi: 10.1021/acs.inorgchem.9b02796.
3. Groza D, Gehrig S, Kudela P, Holcmann M, Pirker C, Dinhof C, Schueffl HH, Sramko M, Hoebart J, Alioglu F, Grusch M, Ogris M, Lubitz W, Keppler BK, Pashkunova-Martic I, Kowol CR, Sibilia M, Berger W, Heffeter P. Bacterial Ghosts as Adjuvant to Oxaliplatin Chemotherapy in Colorectal Carcinomatosis. Oncoimmunology. 2018 Feb 16;7(5):e1424676. doi: 10.1080/2162402X.2018.1424676.
4. Hager S, Korbula K, Bielec B, Grusch M, Pirker C, Schosserer M, Liendl L, Lang M, Grillari J, Nowikovsky K, Pape VFS, Mohr T, Szakács G, Keppler BK, Berger W, Kowol CR, Heffeter P. The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition. Cell Death Dis. 2018 Oct 15;9(11):1052. doi: 10.1038/s41419-018-1102-z.
5. Schoenhacker-Alte B, Mohr T, Pirker C, Kryeziu K, Kuhn P.S., Buck A, Hofmann T, Gerner C, Hermann G, Koellensperger G, Keppler BK, Berger W, Heffeter P. Sensitivity towards the GRP78 inhibitor KP1339/IT-139 is characterized by apoptosis induction via caspase 8 upon disruption of ER homeostasis. Cancer Letters 2017 Sep 28;404:79-88.
6. Mayr J, Heffeter P (Corr. author), Groza D, Galvez L, Koellensperger G, Roller A, Alte B, Haider M, Berger W, Kowol CR, Keppler BK. An albumin-based tumor-targeted oxaliplatin prodrug with distinctly improved anticancer activity in vivo. Chem Sci 2017 Mar 1;8(3):2241-2250.

FG3 Team

Research interests

Gunda Koellensperger addresses analytical metallomic and metabolomic strategies to dissect the key factors for therapy response and resistance with a special focus on single-cell strategies. Her research envisages the development of innovative analytical procedures with emphasis on accurate quantification in omics-type of analysis and cutting-edge elemental mass spectrometry addressing single cell analysis.

Selected publications

1. Theiner S, Schweikert A, Van Malderen SJM, Schoeberl A, Neumayer S, Jilma P, Peyrl A, Koellensperger G, Laser Ablation-Inductively Coupled Plasma Time-of-Flight Mass Spectrometry Imaging of Trace Elements at the Single-Cell Level for Clinical Practice, Analytical Chemistry, 2019, DOI 10.1021/acs.analchem.9b00698
2. Galvez, L., Rusz, M., Schwaiger-Haber, M., El Abiead, Y., Hermann, G., Jungwirth, U., Berger, W., Keppler, B.K., Jakupec, M.A., Koellensperger, G. Preclinical studies on metal based anticancer drugs as enabled by integrated metallomics and metabolomics (2019) Metallomics, 11 (10), pp. 1716-1728. DOI: 10.1039/c9mt00141g
3. Schwaiger M,  Schoeny H, El Abiead Y, Hermann G, Rampler E, Koellensperger G, Merging metabolomics and lipidomics into one analytical run, Analyst [2019], 144, 220-229, DOI: 10.1039/C8AN01219A
4. Theiner S, Van Malderen SJM, Van Acker T, Legin A, Keppler BK, Vanhaecke F, Koellensperger G. Fast High-Resolution Laser Ablation-Inductively Coupled Plasma Mass Spectrometry Imaging of the Distribution of Platinum-Based Anticancer Compounds in Multicellular Tumor Spheroids, [2017] Analytical Chemistry, 89 (23), pp. 12641-12645. DOI: 10.1021/acs.analchem.7b02681
5. 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. [2017] Analytical Chemistry, 89 (14), pp. 7667-7674. DOI: 10.1021/acs.analchem.7b01624

FG3 Team

Research interests

The research of my group focuses on the development of new strategies to overcome severe side effects, resistance development and insufficient tumor accumulation of currently applied anticancer drugs. The strategies include:

• Bioinorganic prodrug development of clinically approved drugs to increase the anticancer activity and prevent the occurrence of severe side effects
• Drug delivery systems like liposomes, polymers and albumin-targeting for tumor-specific accumulation and activation of anticancer drugs

Selected publications

1. Bielec, B.; Schueffl, H.; Terenzi, A.; Berger, W.; Heffeter, P.; Keppler, B. K.; Kowol, C. R (corresponding author). Development and biological investigations of hypoxia-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib Bioorg. Chem. 2020, 99, 103778.
2. Kastner, A.; Poetsch, I.; Mayr, J.; Burda, J. V.; Roller, A.; Heffeter, P.; Keppler, B. K.; Kowol, C. R (corresponding author). A dogma in doubt: aquation of equatorial ligands of Pt(IV) complexes under physiological conditions Angew. Chem. Int. Ed. 2019, 58, 22, 7464-7469.
3. Heffeter, P.; Pape, V. F. S.; Enyedy, E. A.; Keppler, B. K.; Szakacs, G.; Kowol, C. R (corresponding author). Anticancer thiosemicarbazones: chemical properties, interaction with iron metabolism, and resistance development. Antioxid. Redox. Sign. 2019, 30, 1062-1082.
4. Englinger, B.; Pirker, C.; Heffeter, P.; Terenzi, A.; Kowol, C.R.; Keppler, B. K.; Berger, W. Metal drugs and the anticancer immune response. Chem. Rev. 2019, 119, 1519-1624.
5. Kallus, S.; Englinger, B.; Senkiv, J.; Laemmerer, A.; Heffeter, P.; Berger, W.; Kowol, C. R. (corresponding author); Keppler, B. K. Nanoformulations of Anticancer FGFR Inhibitors with Improved Therapeutic Index. Nanomed. Nanotechnol. 2018, 14, 2632-2643.
6. Mayr, J.; Heffeter, P.; Groza, D.; Galvez, L.; Koellensperger, G.; Roller, A.; Alte, B.; Haider, M.; Berger, W.; Kowol, C. R. (corresponding author); Keppler, B. K. An albumin-based tumor-targeted oxaliplatin prodrug with distinctly improved anticancer activity in vivo. Chem. Sci. 2017, 8, 2241–2250.

FG3 Team

Research interests

My group focuses on the development of analytical workflows for the analysis of lipids and glycolipids. Within the FWF research group on the action of metal anti-cancer drugs in the tumor microenvironment, we investigate how tumor-specifically activated drugs impact on the lipidome of cancer cells. For this purpose, we will extend our existing analytical toolbox based on liquid chromatography and high resolution mass spectrometry for lipid profiling in tumor cell compartments such as lipid droplets. Our final goal is to understand lipid-based communication with the tumor microenvironment.

Selected publications

1. M. Rusz, E. Rampler, B.K. Keppler, M. A. Jakupec, G. Koellensperger, Single spheroid metabolomics: Optimizing sample preparation of three-dimensional multicellular tumor spheroids, Metabolites, 2019, 9, 304, doi: 10.3390/metabo9120304
2. E. Rampler, D. Egger, H. Schoeny, M. Rusz, M.P. Pacheco, G. Marino, C. Kasper, T. Naegele, G. Koellensperger, The Power of LC-MS Based Multiomics: Exploring Adipogenic Differentiation of Human Mesenchymal Stem/Stromal Cells, Molecules, 2019, 24, 3615, doi:10.3390/molecules24193615
3. E. Rampler, A. Criscuolo, M. Zeller, Y. El Abiead, H. Schoeny, G. Hermann, E. Sokol, K. Cook, D. A. Peake, B. Delanghe, G. Koellensperger, Analytical Chemistry, 2018, 90, 11, 6494-6501, A novel lipidomics workflow for improved human plasma identification and quantification using RPLC-MSn methods and isotope dilution strategies. Invitation for cover suggestion
   doi: 10.1021/acs.analchem.7b05382
4. E. Rampler*, H. Schoeny, B. M.  Mitic, Y. El Abiead, M. Schwaiger, G. Köllensperger*, Analyst, 2018, 143, 1250-1258, Simultaneous non-polar and polar lipid analysis by on-line combination of HILIC, RP and high resolution MS.doi: 10.1039/c7an01984j.
5. E. Rampler, C. Coman, G. Hermann, A. Sickmann, R. Ahrends, G. Koellensperger, Analyst, 2017, 142, 1891-1899, LILY-Lipidome Isotope Labeling of Yeast: In vivo synthesis of ¹³C labeled reference lipids for quantification by mass spectrometry. Open access. HOT paper
   doi: 10.1039/c7an00107j

FG3 Team