During recent decade, the event-free survival of childhood acute leukemia has improved significantly. However, even with the prevalent usage of specified treatment protocols, treatment gap remains and besides that the conventional therapies used routinely inflict significant toxicity due to low specificity. Therefore, developing new therapeutic strategies and better stratification of the clinically approved drugs, based upon concomitant molecular profiling, which would inflict low toxicity and reduce the relapse rates are of utmost importance.
We, therefore, aimed to develop novel targeted therapies for primary resistant and relapsed leukemia’s, which still have a dismal prognosis with conventional therapies. Novel compound libraries are designed and synthesized by our collaborators (Prof. Dr. Kurz and Prof. Dr. Gohlke, HHU Düsseldorf; JProf. Dr. Hansen, Univeristy of Leipzig). We have established series of biochemical and functional in vitro assays with the selected compounds, while the most potent candidates are subjected to in vivo analysis using Xenograft mouse models. In a distinctive approach, we map dependencies on various signalling pathways by using drug sensitivity/resistance patterns with a library of compounds, which includes clinically approved drugs routinely used to treat leukemia, inhibitors in early to late clinical phase and early promising inhibitors waiting to enter clinical trials.
Applications from motivated candidates are welcome.
Bhatia S, Krieger V, Groll M, Osko JD, Reßing N, Ahlert H, Borkhardt A, Kurz T, Christianson DW, Hauer J, Hansen FK. Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor. J Med Chem. 2018 Nov 8. doi: 10.1021/acs.jmedchem.8b01487. PubMed PMID: 30365892.
Bhatia S, Diedrich D, Frieg B, Ahlert H, Stein S, Bopp B, Lang F, Zang T, Kröger T, Ernst T, Kögler G, Krieg A, Lüdeke S, Kunkel H, Rodrigues Moita AJ, Kassack MU, Marquardt V, Opitz FV, Oldenburg M, Remke M, Babor F, Grez M, Hochhaus A, Borkhardt A, Groth G, Nagel-Steger L, Jose J, Kurz T, Gohlke H, Hansen FK, Hauer J. Targeting HSP90 dimerization via the C terminus is effective in imatinib-resistant CML and lacks the heat shock response. Blood. 2018 Jul 19;132(3):307-320. doi: 10.1182/blood-2017-10-810986. PubMed PMID: 29724897.
García-Ramírez I & Bhatia S, Rodríguez-Hernández G, González-Herrero I, Walter C, González de Tena-Dávila S, Parvin S, Haas O, Woessmann W, Stanulla M, Schrappe M, Dugas M, Natkunam Y, Orfao A, Domínguez V, Pintado B, Blanco O, Alonso-López D, De Las Rivas J, Martín-Lorenzo A, Jiménez R, García Criado FJ, García Cenador MB, Lossos IS, Vicente-Dueñas C, Borkhardt A, Hauer J, Sánchez-García I. Lmo2 expression defines tumor cell identity during T-cell leukemogenesis. EMBO J. 2018 Jul 13;37(14). pii: e98783. doi: 10.15252/embj.201798783. PubMed PMID: 29880602.
• German Consortium Translational Cancer Research, DKTK, Joint funding programme
• German Cancer Aid
• Research Commission of the Faculty of Medicine, HHU Düsseldorf