Medical University of Vienna
Institute for Cancer Research
Department of Medicine I
1090 Vienna, Austria
Phone: +43 1 40160-57594
Fax: +43 1 40160-957502
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:
- Improvement of anticancer activity by smart drug combinations;
- Development of new targeting strategies to increase drug delivery to the tumor tissue (in cooperation with the Institute of Inorganic Chemistry, Vienna within “Forschungsplattform Translational Cancer Therapy Research“;
- 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.
Advertised project “Novel albumin-binding oxaliplatin prodrugs to circumvent resistance”
Enhanced accumulation of albumin in tumors has been successfully exploited to increase the efficacy of paclitaxel (Abraxane) and doxorubicin (Aldoxorubicin). Recently, we have synthesized the first albumin-targeting prodrugs of platinum drugs, which are currently under development to undergo phase I clinical trials, following the demonstration of outstanding in vitro and in vivo anticancer activity. Based on these preliminary data we hypothesize that albumin-bound prodrugs can overcome resistance and thus increase efficacy of platinum drugs. Our laboratory has established a wide range of in vitro and in vivo models to study intrinsic and acquired resistance mechanisms. This unique resource, consisting of more than 20 platinum-resistant cell models (many of them tumorigenic in mice), will serve as a screening platform to investigate the potential of our new drug delivery system to overcome drug resistance mechanisms, which usually hamper the efficacy of platinum drugs. In parallel, new in vitro and vivo models (cell lines, grafts, organoids) with acquired resistance to the albumin-targeting prodrugs will be established and analyzed for the underlying resistance mechanisms. The functional relevance of the most prominent resistance mechanisms will be verified by CRISPR/Cas9 based genome editing. Finally, the anticancer activity, intratumoral accumulation and pharmacokinetics of the novel albumin-binding prodrugs will be evaluated in in vivo resistance models, focusing also on alterations in albumin homeostasis.
- 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.
- 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.
- 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.
- 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.
- Miklos M, Pelivan K, Kowol CR, Pirker C, Dornetshuber-Fleiss R, Spitzwieser M, Englinger B, Van Schoonhoven S, Cichna-Markl M, Köllensperger G, Keppler BK, Berger W, Heffeter P. Triapine-mediated ABCB1 induction via PKC induces widespread therapy unresponsiveness but is not underlying acquired triapine resistance. Cancer Letters 2015 Mar 5. pii: S0304-3835(15)00164-0.
- Karnthaler-Benbakka C, Groza D, Kryeziu K, Pichler V, Roller A, Berger W, Heffeter P (Corr author), Kowol CR. Tumor-Targeting of EGFR Inhibitors via Hypoxia-Mediated Activation. Angew Chem Int Ed Engl. 2014 Nov 17;53(47):12930-5.