Targeting HOTAIRM1 in Glioblastoma Multiforme

• Applicants: Professor Dr. Guido Reifenberger, Ph.D.; Professor Dr. Marc Remke
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Hematology, Oncology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323581543

Glioblastoma multiforme comprises the most common malignant brain tumor. Patients receive multimodal therapies consisting of surgical resection, radio- and chemotherapy. Prognosis of these patients remains bleak despite aggressive therapeutic intervention. The development of risk-adapted and rationale therapies holds great promise to improve the prognosis of this high-risk patient cohort. Despite the growing insights into GBM biology, only few molecular markers inform clinical decision making and targeted therapies have not been successfully implemented as standard of care. Previously depicted as transcriptional noise, it is now clear that long non-coding RNAs (lncRNA) play important roles in many aspects of cell biology and disease. Here, we propose to study the cellular functions of the lncRNA HOXA transcript antisense RNA, myeloid-specific 1 (HOTAIRM1) in the context of glioblastoma and in particular, in Glioblastoma Cancer Stem Cells (gCSC). Our preliminary data suggest that HOTAIRM1 is relevant in glioblastoma as its high expression is correlated with poor prognosis in three independent patient cohorts. Moreover, our preliminary data suggest that glioblastoma tumor cells that lose expression of HOTAIRM1 exhibit less aggressive tumor biology. To elucidate the contribution of HOTAIRM1 to gCSC tumorigenicity, stemness and aggressiveness, we will use cell biology techniques along with genome-wide discovery tools. To unravel the mechanism by which HOTAIRM1 promotes aggressive tumor biology, we will use biochemical approaches and identify its binding partners. Finally, we will confirm that these binding partners are involved in HOTAIRM1 mechanism of action. In summary, these experiments will present a novel important driver in glioblastoma biology, the mechanism of action of a clinically relevant lncRNA, and, potentially, a new opportunity for therapeutic intervention in glioblastoma.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Co-Investigators: Professor Dr. Patrick Roth; Professor Dr. Michael Weller