Kinase networks in pancreatic cancer

Coordinator:		Prof. Dr. Thomas Seufferlein
Institution:		Universitätsklinikum Ulm
Homepage:		www.uniklinik-ulm.de

Protein kinases regulate different biological properties of tumors such as proliferation, invasion and metastasis and therefore represent target molecules for development of new therapeutic strategies for cancer. Pancreas carcinoma is the eighth cause of the cancer-related deaths worldwide having extremely poor prognosis. Based on a Jamboree screen in cooperation with Prof.Gress/Dr.Buchholz in Marburg, six protein kinases were identified to be differentially expressed and featured as potential druggable targets in pancreatic cancer. Detailed characterization of such a kinase, namely PKD2, revealed a key role in the modulation of hypoxia-induced VEGF promoter and protein expression in pancreas carcinoma, thus acting as a “signaling hub” during tumor angiogenesis (GUT, 2010).  Substrate screen approaches revealed 10 new in vitro substrates for PKD2. Focus was directed to Rhotekin’s investigation (JBC, 2012) and CIB1a and its role in tumor cell invasion, angiogenesis and growth (Oncogene, 2013). Furthermore PKD2 controls pancreatic cancer cell invasive properties being a key regulator of trypsin (PRSS1 / PRSS3) as well as of matrix-metalloproteases (MMP7 / MMP9) expression and secretion (submitted). High throughput screen with a Chemical Compound Library has been conducted in collaboration with Dr. Jens von Kries in Berlin in order to identify selective inhibitors for PKD2. The activity of these molecules can be strongly modified upon minute modifications of particular residues. Of 20 homologues tested so far, a variant displayed the IC50 value of 0.3 µM. The detailed in vivo analysis of these compounds was corroborated with the characterization of a genetically engineered mouse with pancreas-specific deletion of PKD1 and expression of K-ras G12D. Another kinase revealed by the Jamboree screen was PKM2. Comprehensive in vivo tumor xenograft analysis suggested a key role of this kinase in the formation of peritumoral blood vessel formation. Ongoing investigations aim at finding new putative substrates for PKM2 as well as the characterization of substrate-independent /–dependent growth of pancreatic cancer cells.