Biologic and therapeutic impact of the AKT1E17K mutation in meningiomas

• Applicant: Professor Dr. Christian Mawrin
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Pathology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329214285

Meningiomas are frequent intracranial tumours, in which a significant proportion of patients may benefit from pharmacological treatment in addition to surgery and irradiation, especially in aggressive meningioma subtypes. However, so far no treatment scheme has been proven to be effective. Our group has recently demonstrated in vitro and in vivo that mTORC1 inhibitors represent an effective meningioma treatment option. The role of genetic factors for biologic aggressiveness and chemosensitivity of meningiomas is not well defined. This applies even to the tumour suppressor NF2 (merlin), despite the high frequency of functional losses of this gene. Recently, the oncogenic mutation E17K in the AKT1 gene (AKT1E17K), which leads to a constitutive activation of this kinase, has been identified as a somatic mutation in a fraction of meningiomas without NF2 loss, suggesting an independent AKT1-driven tumour-promoting pathway. This constitutive activation of AKT1 is highly interesting, because AKT1 interacts bi-directionally with two mTOR-complexes and can be expected to modify mTOR-associated growth regulation and chemosensitivity. In the proposed project, we will analyse a) the role of AKT1E17K for the regulation of mTOR complexes and mTOR-dependent features of meningioma cells, i.e. proliferation, adhesion, migration, invasion, colony formation, and chemosensitivity in vitro, b) in mouse models the impact of AKT1E17K for tumorigenic properties and growth kinetics of meningiomas in tumour-bearing nude mice, and c) the response of the latter parameters in vivo towards inhibitors of AKT1, of mTORC1, or dual inhibitors of mTORC1/2. The in vitro studies will be based upon syngenic cell lines expressing mutant and wild-type AKT1. In vivo experiments will include intracranial xenografts of human tumour cells, as well as a genetically induced mouse meningioma model. The latter will be characterized by meningeal expression of AKT1E17K or AKT1wt. The generation of the mouse model requires the generation of two mouse strains, which contain in all cells the appropriate AKT1 transgene, silenced by a floxed transcriptional stop signal (tpa). They will be crossed with Cre driver mice, which express Cre under the control of the meningeal-specific prostaglandin-D2-synthase (PGDS) promoter. We expect to achieve a specific expression of AKT1wt or AKT1E17K in mouse meninges, allowing modelling of a potential tumour-initiating effect for meningiomas by this oncogene.

• DFG Programme: Research Grants