Genomic characterization of therapeutically-relevant targets in progressive/ high-grade meningioma

• Applicant: Professor Dr. Tareq Juratli
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: Funded in 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 401837860

Meningiomas are the most common primary intracranial tumor. Although many of these tumors are benign, and are cured with the standard therapies of surgical resection and radiation therapy, recurrence is nevertheless relatively common. After failure of frontline treatment, there is unfortunately no current standard therapy to offer patients who have progressive recurrent meningioma, and securing durable, long-term disease control in this setting has been challenging. New therapeutic approaches are needed for these cases. Modern genomic technologies have allowed for broad characterization of somatic gene mutations found in tumor cells in many different cancers. Recent work has identified SMO, AKT1, KLF4 and TRAF7 mutations in low-grade meningiomas, in addition to the well-established NF2 inactivation that is characteristic of this neoplasm. On the other hand, higher-grade and recurrent meningiomas harbor more frequently (up to 28%) TERT promoter (TERTp) mutations, which are predictive of a higher recurrence rate. However, a longitudinal genomic analysis of driver genetic alterations across the spectrum of initial and recurrent disease remains incomplete. In our proposed project, we will focus on understanding the molecular alterations across the clinical spectrum of recurrent meningiomas. Therefore, we characterized a large cohort of patients (n= 120) with progressive/higher-grade meningiomas at both initial diagnosis and recurrence. After pursuing the whole exome sequencing in matched initial and recurrent meningioma pairs, we analyzed the data by established algorithms to evaluate for somatic mutations, copy number alterations and rearrangements. We discovered new interesting candidate genes that we are validating by an orthogonal approach using focused Sanger sequencing and single-nucleotide genotyping. In addition, to confirm our findings, we are performing immunohistochemistry and western blot in large number of samples. Using proliferation and clonogenic assays in models that include meningioma cell lines (e.g. IOMM-Lee), patient-derived meningioma cell lines we have established (MN3 and MN8) and TERT-immortalized non-transformed human arachnoid cells, we will functionally characterize the most significant candidate genes and assess their potential for neoplastic transformation. Deleted or amplified genes in recurrent meningiomas, compared to primary meningiomas, will be genetically over-expressed or silenced, respectively, to determine if that results in an altered phenotype in these models. Our proposed genomic and biological analyses have the potential to identify the genetic factors that drive meningiomas to relapse or undergo malignant transformation, targets which could be prioritized to maximize clinical impact. Thus, the successful execution of this work will provide important information to facilitate the design and interpretation of ongoing clinical trials for recurrent progressive meningiomas.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Daniel Cahill, Ph.D.