Genetics; Leukemia; Receptors, Notch; Therapeutics
- Comprehensive Cancer Center Vienna / Drug & Target Screening Unit
My main focus is the elucidation of the pathomechanism of chronic lymphocytic leukemia (CLL) and to translate the basic research into clinical practise. By taking advantage of reverse genetics, we found that deregulation of NOTCH2 signaling is involved in the overexpression of CD23 in CLL cells. NOTCH2 is implicated in a wide variety of human neoplasias, making NOTCH2 a promising candidate for therapeutic interventions. My work focuses also on the identification of NOTCH2 gain of function mutations leading to the expression of gamma-secretase inhibitor (GSI) resistant nuclear NOTCH2 forms. Moreover, we will evaluate the clinical relevance of our newly identified NOTCH2 transactivation inhibitor Gliotoxin in NOTCH2 associated malignancies like CLL, hepatocellular carcinoma, pancreas carcinoma, and melanoma.
Techniques, methods & infrastructure
Cocultur models to mimic the CLL Tumor microenvironment. FACS, RT-PCR, EMSA, Western bloting, sequence analysis, gene silencing for functional studies with siRNA, drug screening assays.
- Hubmann, R. et al., 2012. Gliotoxin is a potent NOTCH2 transactivation inhibitor and efficiently induces apoptosis in chronic lymphocytic leukaemia (CLL) cells. Br J Haematol, 160(5), pp.618-629. Available at: http://dx.doi.org/10.1111/bjh.12183.
- Hubmann, R. et al., 2010. NOTCH2 links protein kinase C delta to the expression of CD23 in chronic lymphocytic leukaemia (CLL) cells. British Journal of Haematology, 148(6), pp.868-878. Available at: http://dx.doi.org/10.1111/j.1365-2141.2009.08024.x.
- Duechler, M. et al., 2004. Induction of apoptosis by proteasome inhibitors in B-CLL cells is associated with downregulation of CD23 and inactivation of Notch2. Leukemia, 19(2), pp.260-267. Available at: http://dx.doi.org/10.1038/sj.leu.2403592.
- Hubmann, R. et al., 2002. Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Blood. 2002 May 15;99(10):3742-7.
- Hubmann, R. et al., 2017. Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model. Frontiers in Pharmacology, 8. Available at: http://dx.doi.org/10.3389/fphar.2017.00319.