Selectively releasing resistance to TRAIL-mediated apoptosis in cancer cells as therapeutic option for hepatocellular carcinoma
Final Report Abstract
Our research focussed on the possibility of selectively inducing apoptosis in cancer cells by the use of agents targeting the receptors for the TNF-related apoptosis inducing ligand (TRAIL). These agents were developed as promising cancer therapy and made available for clinical investigation. Specifically, our efforts aimed to assess the contribution of the loss of TRAIL- receptors expression to the development of HCC and of other tumors of gastroenterological origin and its significance as potential obstacle to the administration of TRAIL-receptors targeting compounds. Also, oncogenes frequently overexpressed in gastrointestinal tumors were assessed with respect to their potential role in the development of resistance to receptormediated apoptosis. We found that the proapoptotic effect of TRAIL and thus its therapeutic potential can be hampered at different stages of the pro-apoptotic cascade. At the cell membrane, due to the loss of functional receptors exposed to the outer cell surface; within the cell by the overexpression of JNK, Raf, and MET, which impinge on several stages of the intrinsic and extrinsic apoptotic signalling. The results achieved in the contest of this grant are relevant to the selection of patients eligible for treatment with TRAIL-receptors targeting agents. They also provide the rationale for the association of such compounds with sensitizers capable of releasing the resistance to specific steps of apoptosis induction to establish personalized cancer treatment schemas.
Publications
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JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand. Gut. 2009 May;58(5):688-98
Mucha SR, Rizzani A, Gerbes AL, Camaj P, Thasler WE, Bruns CJ, Eichhorst ST, Gallmeier E, Kolligs FT, Göke B, De Toni EN
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Expression, cellular distribution, and prognostic relevance of TRAIL receptors in hepatocellular carcinoma. Clin Cancer Res. 2010 Nov 15;16(22):5529-38
Kriegl L, Jung A, Engel J, Jackstadt R, Gerbes AL, Gallmeier E, Reiche JA, Hermeking H, Rizzani A, Bruns CJ, Kolligs FT, Kirchner T, Göke B, De Toni EN
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The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells. Endocr Relat Cancer. 2011 Mar 21;18(2):277-85
Zitzmann K, De Toni E, von Rüden J, Brand S, Göke B, Laubender RP, Auernhammer CJ
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Microsatellite instability, KRAS mutations and cellular distribution of TRAIL-receptors in early stage colorectal cancer. PLoS One. 2012;7(12):e51654
Kriegl L, Jung A, Horst D, Rizzani A, Jackstadt R, Hermeking H, Gallmeier E, Gerbes AL, Kirchner T, Göke B, De Toni EN
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Loss of TRAIL-receptors is a recurrent feature in pancreatic cancer and determines the prognosis of patients with no nodal metastasis after surgery. PLoS One. 2013;8(2):e56760
Gallmeier E, Bader DC, Kriegl L, Berezowska S, Seeliger H, Göke B, Kirchner T, Bruns C, De Toni EN
