Novel therapeutic strategies in gliomas, based on the inhibition of the oncogenic signal transduction pathways Pim-1 / STAT3 through RNA interference and miRNA replacement

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Malignant gliomas are characterized by their strong resistance towards conventional therapies, resulting in an extremely poor prognosis. Thus, the detailed analysis of relevant signal transduction pathways is an indispensable basis for future targeted and personalized therapeutic approaches. In our previous studies, we were able to gain substantial insight into the functional relevance of the serine/threonine kinase Pim-1 in other solid tumors (colon carcinoma), and to elucidate the pivotal role of the oncogenic transcription factor STAT3 and the STAT3 target gene Mcl-1 in mediating resistance of gliomas towards chemotherapy. Furthermore, our studies indicate that Pim-1 is overexpressed in gliomas, demonstrate regulatory functions of the miRNAs miR-33a and miR-15b on the Pim-1 expression and strongly suggest an extensive cellular crosstalk between Pim-1 and STAT3. In gliomas, however, this has neither been investigated nor explored therapeutically. This project focuses on the oncological relevance of the Pim-1/STAT3/Mcl-1 signal transduction axis in gliomas, using different in vitro cell models, syngenic in vivo glioma models, mouse xenograft models and primary tumor material derived from glioma patients. Beyond functional analyses, the therapeutic implications of this signal axis as a target for therapeutic intervention will be explored. To this end, RNAi-mediated gene knockdown, pharmacological inhibition, miRNA replacement and nanoparticulate systems for the delivery of siRNAs/miRNAs will be employed, also in combination with established chemotherapy and aiming at the development of novel therapeutic strategies. More specifically, this project will analyse the molecular effects of a Pim-1 inhibition on the cellular signal transduction of glioma cells with regard to the downstream effectors STAT3 and Mcl-1, and correlate them with alterations in cell proliferation, -migration, -invasion and resistance towards apoptosis. Furthermore, the functional role of the Pim-1-relevant miRNAs miR-33a and miR-15b will be determined in gliomas, and the efficacy of the blockage of the Pim-1/STAT3/Mcl-1 axis by miRNA replacement will be analysed and compared with the other strategies of Pim-1 inhibition. The inhibition of the signal axis will also be studied with regard to synergistic effects through sensitization towards conventional chemotherapy. Therapeutically, the Pim-1/STAT3/Mcl-1 axis will be explored in preclinical mouse models by employing nanoparticulate systems for the delivery of siRNAs/miRNAs in vivo, alone or in combination with temozolomid, aiming at the establishment of novel, nanocarrier-based strategies for the therapy of malignant gliomas.