in treatment regimens for pancreatic cancer cells
The sorely complex nature of carcinomas of the pancreas, arising from concomitant accumulation of multiple genetic and epigenetic disorders mediates potent chemo-resistance towards standard first-line chemotherapy approaches and defines a desperate need for novel chemotherapeutic agents targeting specific cellular survival pathways.
Previous studies applying pharmacological inhibition and RNAi-mediated silencing of CK2 have identified the protein kinase as a lateral modulator of apoptotic cell death in in vitro models of pancreatic cancer. In this study, the role of protein kinase CK2 in chemo-resistance towards gemcitabine was characterized and a prominent cooperation between CK2 and the PI3K/AKT as well as MAPK/JNK pro-survival pathways was revealed. Modulation of CK2 expression and activity resulted in increased chemo-sensitization and these findings present promising objectives for novel combination therapy regimens.
Many cancer types, including pancreatic cancer cells express high levels of polyamines and a variety of anti-tumor strategies mediating the pharmacological depletion of these poly-cationic pools have been developed. This study identified and characterized implications of CK2 expression and activity levels in the efficacy of chemotherapeutic agents in colon and pancreatic cancer. Modulation of polyamine pools resulted in transcriptional and translational changes of CK2 expression and further evidence for its role as a potent pro-survival protein was documented.
Novel chemotherapeutic agents have recently been developed in order to combine in a single molecule the DNA-alkylating functions of
established agents with the potent inhibition of growth factor receptor tyrosine kinases. This study characterized AS104, a novel agent of the 2-triazenoazaindole class with respect to its efficacy in inducing cell death in pancreatic cancer cells. AS104 was documented to potently mediate the induction of apoptosis as well as autophagy in an in vitro model of pancreatic cancer. Moreover, lowered mRNA expression levels of the human epidermal growth factor receptor family members EGFR and HER2 pointed out a possible role of the drug in transcriptional regulation of the corresponding genes.
Jan Nicolas Kreutzer
Institut for Biokemi og Molekylær Biologi
Dekanen nedsatte den 15. juni 2011 et bedømmelsesudvalg bestående af professor Stephen Douthwaite, Institut for Biokemi og Molekylær Biologi, Syddansk Universitet, PhD David W. Meek, Medical Research Institute & Dundee Cancer Centre, University of Dundee, Storbritannien og Professor Jens Høiriis Nielsen, Biomedicinsk Institut, Panum Instituttet til at bedømme den af Jan Nicolas Kreutzer indleverede afhandling ”Importance of protein kinase-mediated signaling pathways in treatment regimens for pancreatic cancer cells”. I bedømmelsesudvalgets arbejde deltog endvidere uden stemmeret Jan Nicolas Kreutzer’s vejleder, lektor Barbara Guerra, Institut for Biokemi og Molekylær Biologi, Syddansk Universitet.
Den 25. november 2011 holdt Jan Nicolas Kreutzer en forelæsning over emnet ”Pancreatic cancer – unraveling new synergies for a refractory disease”.
Efter indstilling fra bedømmelsesudvalget tildelte dekanen herefter den 6. december 2011 Jan Nicolas Kreutzer ph.d.-graden.
Jan Nicolas Kreutzer, født 24. august 1983 i Saarbrücken, Tyskland. Abitur, Christian von Mannlich Gymnasium, Homburg/Saar, 2002. Kemisk studerende ved Technical University of Kaiserslautern og German Heart Centre Munich, 2002 - 2008. Ph.D. stipendiat ved Barbara Guerra, Ph.D., Institut for Biokemi og Molekylær Biologi, Syddansk Universitet, september 2008 - august 2011. Udlandsophold hos Prof. David W. Litchfield, University of Western Ontario, september - december 2010