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Terasawa A, Shimazu K, Nanjo H, Miura M, Shibata H. Diarylpentanoid, a curcumin analog, inhibits malignant meningioma growth in both in vitro and in vivo models. World J Exp Med 2025; 15:102897. [DOI: 10.5493/wjem.v15.i2.102897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/31/2024] [Accepted: 01/21/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Malignant meningioma metastasizes systemically, primarily due to its role in epithelial-mesenchymal transition. Although the prognosis is extremely poor, drug development efforts have been limited, because this tumor is categorized as a rare form.
AIM To examine growth suppressive effect of GO-Y030, a diarylpentanoid curcumin analog, (1E,4E)-1,5-bis [3,5-bis (methoxymethoxy) phenyl] penta-1,4-dien-3-one against the malignant meningioma.
METHODS The growth suppression of malignant meningioma cells by GO-Y022 and GO-Y030 were examined, using IOMM-Lee and HKBMM cell lines. Male nude mice aged eight weeks, specifically BALB/cSlc-nu/nu mice received a subcutaneous inoculation of IOMM-Lee (107 cells/site) on their back and 30 μg/kg of recombinant hepatocellular growth factor (HGF) was injected into the tumor every three days. After confirmed the growth tumor mass, 500 μL of GO-Y030 diluted with PBS were administrated intraperitoneally daily at doses of 1 mg/kg and 2 mg/kg, respectively.
RESULTS GO-Y030 exhibits a growth inhibitory effect on malignant meningioma cell lines, IOMM-Lee and HKBMM ranging from 0.8-2.0 μM in vitro. Notably, GO-Y030’s inhibitory effect is about 10 to 16th times more potent than that of curcumin, which has previously demonstrated potential in combating malignant meningioma. In mouse models, the intraperitoneal administration of GO-Y030 effectively suppresses the growth of malignant meningioma tumors that have been inoculated in the back (P = 0.002). High-performance liquid chromatography analysis has confirmed the distribution of GO-Y030 in the bloodstream and brain tissue. Moreover, GO-Y030 demonstrates the ability to significantly suppress HGF (P < 0.01), nuclear factor kappa B (P < 0.001), and N-cadherin (P < 0.001), all of which contribute to the epithelial-mesenchymal transition.
CONCLUSION GO-Y030 holds promise as a potent compound for the systemic inhibition of malignant meningioma. GO-Y030 has higher tumor growth inhibitory effect against meningiomas than curcumin, which is known to have antitumor activity through multi-molecular target control resulting in apoptosis induction. GO-Y030 controls at least three molecules of HGF, nuclear factor kappa B, and N-cadherin.
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Affiliation(s)
- Anna Terasawa
- Department of Clinical Oncology, Akita University, Akita 010-8543, Japan
| | - Kazuhiro Shimazu
- Department of Clinical Oncology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Hiroshi Nanjo
- Department of Pathology, Akita University, Akita 010-8543, Japan
| | - Masatomo Miura
- Department of Pharmacokinetics, Graduate School of Medicine, Akita University, Akita, Japan
| | - Hiroyuki Shibata
- Department of Clinical Oncology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
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Sahm F, Bertero L, Brandner S, Capper D, Goldbrunner R, Jenkinson MD, Kalamarides M, Lamszus K, Albert NL, Mair MJ, Berghoff AS, Mawrin C, Wirsching HG, Maas SLN, Raleigh DR, Reifenberger G, Schweizer L, Suwala AK, Tabatabai G, Tabouret E, Short S, Wen PY, Weller M, Le Rhun E, Wesseling P, van den Bent M, Preusser M. European Association of Neuro-Oncology guideline on molecular testing of meningiomas for targeted therapy selection. Neuro Oncol 2025; 27:869-883. [PMID: 39577862 PMCID: PMC12083233 DOI: 10.1093/neuonc/noae253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Indexed: 11/24/2024] Open
Abstract
Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to a lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy, or radioligand therapy. Here, we review the evidence for a predictive role of a wide range of molecular alterations and markers including NF2, AKT1, SMO, SMARCE1, PIK3CA, CDKN2A/B, CDK4/6, TERT, TRAF7, BAP1, KLF4,ARID1/2, SUFU, PD-L1, SSTR2A, PR/ER, mTOR, VEGF(R), PDGFR, as well as homologous recombination deficiency, genomic copy number variations, DNA methylation classes, and combined gene expression profiles. In our assessment based on the established ESMO ESCAT (European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets) evidence-level criteria, no molecular target reached ESCAT I ("ready for clinical use") classification, and only mTOR pathway activation and NF2 alterations reached ESCAT II ("investigational") classification, respectively. Our evaluations may guide targeted therapy selection in clinical practice and clinical trial efforts and highlight areas for which additional research is warranted.
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Affiliation(s)
- Felix Sahm
- Department of Neuropathology, University Hospital Heidelberg, Heidelberg Gemany and CCU Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Luca Bertero
- Pathology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Sebastian Brandner
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology and Division of Neuropathology, University College London Hospitals NHS Foundation Trust, London, UK
| | - David Capper
- German Cancer Consortium (DKTK), partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Roland Goldbrunner
- Department of Neurosurgery, University Hospital Cologne, Cologne, Germany
| | - Michael D Jenkinson
- Department of Neurosurgery, University of Liverpool and Walton Centre, Liverpool, UK
| | - Michel Kalamarides
- Department of Neurosurgery, Pitie-Salpetriere Hospital, AP-HP Sorbonne Université, Paris, France
| | - Katrin Lamszus
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nathalie L Albert
- Department of Nuclear Medicine, LMU Hospital, LMU Munich, Munich, Germany
| | - Maximilian J Mair
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
- Department of Nuclear Medicine, LMU Hospital, LMU Munich, Munich, Germany
| | - Anna S Berghoff
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Christian Mawrin
- Department of Neuropathology, University Hospital Magdeburg, Magdeburg, Germany
| | - Hans-Georg Wirsching
- Department of Neurology, Brain Tumor Center & Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Sybren L N Maas
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
| | - David R Raleigh
- Departments of Radiation Oncology, Neurological Surgery, and Pathology, University of California, San Francisco, San Francisco, California, USA
| | - Guido Reifenberger
- Institute of Neuropathology, Medical Faculty, Heinrich Heine University and University Hospital Düsseldorf, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
| | - Leonille Schweizer
- Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
| | - Abigail K Suwala
- Department of Neuropathology, University Hospital Heidelberg, Heidelberg Gemany and CCU Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Ghazaleh Tabatabai
- Department of Neurology & Interdisciplinary Neuro-Oncology, University Hospital Tübingen, Center for Neuro-Oncology, Comprehensive Cancer Center Tübingen-Stuttgart, DKTK partner site Tübingen, University of Tübingen, Germany
| | - Emeline Tabouret
- Aix-Marseille Universite, APHM, CNRS, INP, Institut Neurophysiopathol, GlioME Team, Plateforme PETRA, CHU Timone, Service de Neurooncologie, Marseille, France
| | - Susan Short
- Department of Oncology, Leeds Institute of Medical Research at St James’s Hospital, Leeds, UK
| | - Patrick Y Wen
- Center For Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Michael Weller
- Department of Neurology, Brain Tumor Center & Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Emilie Le Rhun
- Department of Medical Oncology and Hematology, Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Pieter Wesseling
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Pathology, Amsterdam University Medical Centers/VUmc, Amsterdam, The Netherlands
| | - Martin van den Bent
- The Brain Tumor Center at Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, The Netherlands
| | - Matthias Preusser
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
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Buzatu IM, Tataranu LG, Duta C, Stoian I, Alexandru O, Dricu A. A Review of FDA-Approved Multi-Target Angiogenesis Drugs for Brain Tumor Therapy. Int J Mol Sci 2025; 26:2192. [PMID: 40076810 PMCID: PMC11899917 DOI: 10.3390/ijms26052192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/16/2025] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
Neovascularization is an important process in brain tumor development, invasion and metastasis. Several research studies have indicated that the VEGF signaling target has potential for reducing angiogenesis in brain tumors. However, targeting VEGF signaling has not met the expected efficacy, despite initial enthusiasm. This is partly because tumors cleverly use alternative growth factor pathways, other than VEGF signaling, to restore angiogenesis. Multi-target inhibitors have been developed to inhibit several receptor kinases that play a role in the development of angiogenesis. By simultaneously affecting various receptor kinases, these treatments can potentially obstruct various angiogenic pathways that are involved in brain cancer advancement, often offering a more holistic strategy than treatments focusing on just one kinase. Since 2009, the FDA has approved a number of multi-kinase inhibitors that target angiogenic growth factor receptors (e.g., VEGFR, PDGFR, FGFR, RET, c-KIT, MET, AXL and others) for treatment of malignant diseases, including brain cancer. Here, we present some recent results from the literature regarding the preclinical and clinical effects of these inhibitors on brain tumors.
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Affiliation(s)
- Iuliana Mihaela Buzatu
- Department of Microbiology, “Fundeni” Clinical Institute, Șoseaua Fundeni 258, 022328 Bucharest, Romania;
| | - Ligia Gabriela Tataranu
- Department of Neurosurgery, Clinical Emergency Hospital “Bagdasar-Arseni”, Soseaua Berceni 12, 041915 Bucharest, Romania;
- Department of Neurosurgery, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Carmen Duta
- Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 020022 Bucharest, Romania; (C.D.); (I.S.); (A.D.)
| | - Irina Stoian
- Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 020022 Bucharest, Romania; (C.D.); (I.S.); (A.D.)
| | - Oana Alexandru
- Department of Neurology, University of Medicine and Pharmacy of Craiova, Petru Rares 2, 200349 Craiova, Romania
| | - Anica Dricu
- Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 020022 Bucharest, Romania; (C.D.); (I.S.); (A.D.)
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Okano A, Miyawaki S, Teranishi Y, Ohara K, Hongo H, Sakai Y, Ishigami D, Nakatomi H, Saito N. Advances in Molecular Biological and Translational Studies in World Health Organization Grades 2 and 3 Meningiomas: A Literature Review. Neurol Med Chir (Tokyo) 2022; 62:347-360. [PMID: 35871574 PMCID: PMC9464479 DOI: 10.2176/jns-nmc.2022-0114] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/10/2022] [Indexed: 11/29/2022] Open
Abstract
The treatment of World Health Organization (WHO) grades 2 and 3 meningiomas remains difficult and controversial. The pathogenesis of high-grade meningiomas was expected to be elucidated to improve treatment strategies. The molecular biology of meningiomas has been clarified in recent years. High-grade meningiomas have been linked to NF2 mutations and 22q deletion. CDKN2A/B homozygous deletion and TERT promoter mutations are independent prognostic factors for WHO grade 3 meningiomas. In addition to 22q loss, 1p, 14p, and 9q loss have been linked to high-grade meningiomas. Meningiomas enriched in copy number alterations may be biologically invasive. Furthermore, several new comprehensive classifications of meningiomas have been proposed based on these molecular biological features, including DNA methylation status. The new classifications may have implications for treatment strategies for refractory aggressive meningiomas because they provide a more accurate prognosis compared to the conventional WHO classification. Although several systemic therapies, including molecular targeted therapies, may be effective in treating refractory aggressive meningiomas, these drugs are being tested. Systemic drug therapy for meningioma is expected to be developed in the future. Thus, this review aims to discuss the distinct genomic alterations observed in WHO grade 2 and 3 meningiomas, as well as their diagnostic and therapeutic implications and systemic drug therapies for high-grade meningiomas.
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Affiliation(s)
- Atsushi Okano
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo
| | - Satoru Miyawaki
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo
| | - Yu Teranishi
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo
| | - Kenta Ohara
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo
| | - Hiroki Hongo
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo
| | - Yu Sakai
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo
| | - Daiichiro Ishigami
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo
| | - Hirofumi Nakatomi
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo
- Department of Neurosurgery, Kyorin University
| | - Nobuhito Saito
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo
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Graillon T, Tabouret E, Chinot O. Chemotherapy and targeted therapies for meningiomas: what is the evidence? Curr Opin Neurol 2021; 34:857-867. [PMID: 34629433 DOI: 10.1097/wco.0000000000001002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
PURPOSE OF REVIEW Although most meningiomas are slow growing tumors mainly controlled by surgery with or without radiotherapy, aggressive meningiomas that fail these conventional treatments constitute a rare situation, a therapeutic challenge and an unmet need in neuro-oncology. RECENT FINDING Mutational landscape in recurrent high-grade meningiomas includes mainly NF2 mutation or 22q chromosomal deletion, whereas telomerase reverse transcriptase promoter, BAP-1 and CDK2NA mutations were also found in aggressive meningiomas. Pi3K-Akt-mTOR pathway is currently the most relevant intracellular signaling pathway target in meningiomas with preliminary clinical activity observed. Assessment of drug activity with progression free survival rate at 6 months is challenging in regard to meningioma growth rate heterogeneity, so that 3-dimensional growth rate before and during treatment could be considered in the future to selected new active drugs. SUMMARY Despite a low evidence level, some systemic therapies may be considered for patients with recurrent meningioma not amenable to further surgery or radiotherapy. In recurrent high-grade meningioma, everolimus-octreotide combination, bevacizumab, sunitinib and peptide receptor radionuclide therapy exhibit a signal of activity that may justify their clinical use. Despite a lack of clear signal of activity to date, immunotherapy may offer new perspectives in the treatment of these refractory tumors.
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Affiliation(s)
- Thomas Graillon
- Aix Marseille Univ, APHM, INSERM, MMG, UMR1251, La Timone Hospital, neurosurgery department Marseille, France
| | - Emeline Tabouret
- Aix-Marseille Univ, APHM, CNRS, INP, Inst Neurophysiopathol, La Timone Hospital, Neurooncology Department, Marseille, France
| | - Olivier Chinot
- Aix-Marseille Univ, APHM, CNRS, INP, Inst Neurophysiopathol, La Timone Hospital, Neurooncology Department, Marseille, France
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