The cell death and cancer group studies the mechanism of signal transduction in order to understand the driving forces of cancer progression and to identify targets for therapy. Our current studies examine themechanism of death receptor activation and how the kinetics of death receptor activation regulates apoptosis induction using cell biology assays in combination with crystallography and mathematical modelling. Based on this information we are developing novel therapeutics that can channel the death receptor-mediated signal transduction towards apoptosis by blocking inflammatory signalling.
Secondly, we would like to better understand tumour behaviour in respect to apoptosis resistance to enable prediction of the tumour’s response to apoptosis-inducing therapeutics. We found that while the absolute expression level of proteins is only a weak predictor of resistance, the expression ratio of interacting proteins, or proteins participating in the same signal transduction pathway tightly correlate with apoptosis resistance. By quantitative mass spectrometric analysis we would like to identify the predictive expression ratios and thus develop a ratiometric prediction model of tumour behaviour.
Selection of key publications:
Mahalingam D, Keane M, Natoni A, Samali A and Szegezdi E (2010) Egr-1 blocks DR5-mediated apoptosis by upregulating the short isoform of c-FLIP. (in press Br J Cancer).
Mahalingam D, Keane M, Pirianov G, Mehmet H, Samali A and Szegezdi E (2009) Differential activation of JNK1 isoforms by TRAIL receptors modulate apoptosis of colon cancer cell lines. British J Cancer. 100:1415-24.
Reis CR#, Szegezdi E#, van der Sloot AM#, Natoni A, Tur V, Cool RH, Samali A, Serrano L and Quax WJ (2009) Enhancement of anti-tumour properties of rhTRAIL by affinity increase towards both its death receptors. Biochemistry. 48: 2180-91. #these authors contributed equally
Mahalingam D, Szegezdi E, Keane M, de Jong S and Samali A (2009) TRAIL receptor signalling and modulation: Are we on the right TRAIL? (in Press) Cancer Treatment Rev. 35:280-8.
Tur V, van der Sloot AM, Reis CR, Szegezdi E, Cool RH, Serrano L Samali A and Quax W (2008) Structure based design of a DR4 selective TRAIL variant. JBC 283: 20560-8.
Mylotte LA, Duffy AM, Murphy M, O’Brien T, Samali A, Barry F and Szegezdi E (2008) Metabolic Flexibility Permits MSC Survival in an Ischemic Environment. Stem Cells 26: 1325-36.
Szegezdi E, Mahalingam D, Van der Sloot A, Quax W, Keane M, Samali A (2007) Decoy-insensitive TRAIL variants kill tumour cells more efficiently without damaging non-transformed cells. Proceedings of the American Association for Cancer Research. Annual Meeting; 48: 1224.
Szegezdi E, Cahill S, Meyer M, O’Dwyer M, Samali A (2006) TRAIL sensitization by arsenic trioxide is caspase-8 dependent and involves modulation of death receptor components and Akt. British Journal of Cancer, 94: 398 – 406.
van der Sloot AM, Tur V, Szegezdi E, Mullally MM, Samali A, Serrano L, Quax W. (2006) Computational design of a DR5 receptor selective TRAIL variant. PNAS, 103: 8634–8639.
Ní Chonghaile T, Concannon CG, Szegezdi E, Gorman AM and Samali A (2006) Dexamethasone inhibits apoptosis in C6 glioma cells through increased expression of Bcl-XL. Apoptosis, 11: 1247-1255.
1. Szegezdi E, Mahalingam D, Natoni A and Samali A (2008) Treatment of proliferative disorders with TRAIL. (UK Patent Application No. 0818649.6)
2. van der Sloot AM, Tur V, Szegezdi E, Samali A, Serrano L, Quax W (2007) New design of DR4 selective variants. (GB-0723059.2)
3. van der Sloot AM, Tur V, Szegezdi E, Mullally MM, Samali A, Serrano L, Quax W (2003) Improved cytokine design (WO2005056596)