title: Durable Control of Metastatic AKT1-Mutant WHO Grade 1 Meningothelial Meningioma by the AKT Inhibitor, AZD5363.
abstract: High-throughput analyses have revealed the presence of activating mutations in the AKT1 gene in a subpopulation of meningiomas. We report a female patient with multiple intracranial tumor manifestations and histologically verified meningotheliomatous meningioma in the lung. The tumor was continuously growing at multiple sites despite six surgical resections, radiotherapy, and two lines of systemic therapy. Following detection of an AKT1E17K mutation in three independent tumor samples by sequencing, treatment with AZD5363, a selective AKT inhibitor, was initiated. Ex vivo cultured meningioma cells exhibited sensitivity to the drug as shown by pAKT accumulation on immunoblots. Treatment with AZD5363 resulted, for the first time, in stable disease and minor radiographic response. The patient has been on that treatment for more than one year with ongoing clinical and radiographic response. This is the first report of an AKT1-mutant meningioma responding to AKT inhibition, suggesting that molecular screening may result in clinical benefit.
authors.affiliation: Departments of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.affiliation: Departments of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roth
authors.affiliation: Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.|Clinical cooperation Unit Neuropathology, German Cancer Center (DKFZ), and DKTK, Heidelberg, Germany
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.affiliation: Departments of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Burghardt
authors.affiliation: Department of Radiology, MRI Zurich, Medical Radiological Institute, Zurich, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schuknecht
authors.affiliation: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Rushing
authors.affiliation: Departments of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Regli
authors.affiliation: Oncology, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Melbourn Science Park, Melbourn, UK.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Lindemann
authors.affiliation: Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.|Clinical cooperation Unit Neuropathology, German Cancer Center (DKFZ), and DKTK, Heidelberg, Germany
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008579:Meningioma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D009154:Mutation; D060787:Neoplasm Grading; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D011758:Pyrroles; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C575618:capivasertib