Exploring and Targeting Novel Cancer Networks in Multidrug Resistant Neuroblastoma

Abstract

High-risk neuroblastoma has an overall survival of only 50%, and alternative treatment options for this patient group are needed. In this thesis, I will present novel insight into potential anti-tumor mechanisms for high-risk neuroblastoma. Firstly, our investigations have revealed a tumor suppressor function of the microRNA (miRNA) <i>miR-323a-3p</i> in neuroblastoma cells, and that this miRNA directly targets the oncogene STAT3. Secondly, we have shown that upregulation of another miRNA, <i>miR-193b-3p</i>, made neuroblastoma cells with a primary dependence on the anti-apoptotic protein MCL-1 more sensitive to the BH3 mimetic ABT-737. Lastly, we have tested the ribosome biogenesis inhibitors CX-5461 and quarfloxin in neuroblastoma and found that they effectively inhibit growth in neuroblastoma cells with MYCN amplification, an aberration that is commonly found in high-risk neuroblastoma. These inhibitors reduced levels of MYCN protein and caused DNA damage, G2-cell cycle arrest and apoptosis in neuroblastoma cells. Furthermore, we have demonstrated that they reduce tumor growth in murine neuroblastoma xenograft models. The most profound anti-tumor effects of CX-5461 and quarfloxin were observed in cells and tumors with MYCN amplification and a functional p53 protein, a combination that is often found in high-risk neuroblastoma.