Fatty acid synthase as a novel target for meningioma therapy

Haase, Daniela; Schmidl, Stefan; Ewald, Christian; Kalff, Rolf; Huebner, Christian; Firsching, Raimund; Keilhoff, Gerburg; Evert, Matthias; Paulus, Werner; Gutmann, David H.; Lal, Anita; Mawrin, Christian

doi:10.1093/neuonc/noq004

Cited by 31 publications

(29 citation statements)

References 32 publications

(39 reference statements)

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“…They found that the growth of orthotopic xenografts of malignant mesothelioma cells was strongly inhibited in mice treated with the Fasn inhibitor C75. In addition, Haase et al reported that Fasn expression was elevated in 70% of atypical grade II and anaplastic grade III meningiomas, and that treatment with cerulenin significantly decreased NF2 -null meningioma cell survival in vitro and reduced tumor volumes in xenografts (50). These results, combined with our data in Nf2 -null MEFs and Schwann cells, suggest that changes in lipid synthesis may be a general function in cells lacking Merlin.…”

Section: Discussionmentioning

confidence: 99%

An Essential Role for the Tumor-Suppressor Merlin in Regulating Fatty Acid Synthesis

et al. 2017

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Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas and meningiomas. Mutational inactivation of the NF2 gene encoding the protein Merlin is found in most sporadic and inherited schwannomas, but the molecular mechanisms underlying neoplastic changes in schwannoma cells remain unclear. We report here that Nf2-deficient cells display elevated expression levels of key enzymes involved in lipogenesis and that this upregulation is caused by increased activity of Torc1. Inhibition or knockdown of fatty acid synthase (FASN), the enzyme that catalyzes the formation of palmitic acid from malonyl-CoA, drove NF2-deficient cells into apoptosis. Treatment of NF2-mutant cells with agents that inhibit the production of malonyl-CoA reduced their sensitivity to FASN inhibitors. Collectively, these results suggest that the altered lipid metabolism found in NF2-mutant cells renders them sensitive to elevated levels of malonyl-CoA, as occurs following blockade of fatty acid synthase, suggesting new targeted strategies in the treatment of NF2-deficient tumors.

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Section: Discussionmentioning

confidence: 99%

An Essential Role for the Tumor-Suppressor Merlin in Regulating Fatty Acid Synthesis

et al. 2017

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“…For Western blotting and real-time PCR, 25 meningiomas of different WHO grades were analyzed. Immunohistochemistry was conducted using a tissue microarray (TMA) as previously described (17). The TMA comprised 53 meningioma samples: 30 tumors were grade I (10 meningothelial, 7 fibroblastic, 7 transitional, 3 angiomatous, 1 microcystic, 2 secretory subtypes), 14 were atypical grade II, and 9 were anaplastic grade III meningiomas according to the recent WHO classification (1).…”

Section: Tumor Materials and Immunohistochemical Studiesmentioning

confidence: 99%

mTORC1 Inhibitors Suppress Meningioma Growth in Mouse Models

Pachow

Andrae

Kliese

et al. 2013

Clinical Cancer Research

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Purpose: To evaluate the mTORC1 (mammalian target of rapamycin complex 1) pathway in meningiomas and to explore mTORC1 as a therapeutic target in meningioma cell lines and mouse models.Experimental Design: Tissue microarrays (53 meningiomas of all WHO grades) were stained for phosphorylated polypeptides of mTOR, Akt, and the mTORC1 targets 4EBP1 and p70S6K, the latter being the consensus marker for mTORC1 activity. Expression of proteins and mRNAs was assessed by Western blotting and real-time PCR in 25 tumors. Cell lines Ben-Men-1 (benign), IOMM-Lee and KT21 (malignant), and pairs of merlin-positive or -negative meningioma cells were used to assess sensitivity toward mTORC1 inhibitors in methyl-tetrazolium and bromodeoxyuridine (BrdUrd) assays. The effect of temsirolimus (20 mg/kg daily) on tumor weight or MRI-estimated tumor volume was tested by treatment of eight nude mice (vs. 7 controls) carrying subcutaneous IOMM-Lee xenografts, or of eight (5) mice xenotransplanted intracranially with IOMM-Lee (KT21) cells in comparison to eight (5) untreated controls.Results: All components of the mTORC1 pathway were expressed and activated in meningiomas, independent of their WHO grade. A significant dosage-dependent growth inhibition by temsirolimus and everolimus was observed in all cell lines. It was slightly diminished by merlin loss. In the orthotopic and subcutaneous xenograft models, temsirolimus treatment resulted in about 70% growth reduction of tumors (P < 0.01), which was paralleled by reduction of Ki67 mitotic index (P < 0.05) and reduction of mTORC1 activity (p70S6K phosphorylation) within the tumors.Conclusion: mTORC1 inhibitors suppress meningioma growth in mouse models, although the present study did not measure survival.

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“…FAS inhibitor (cerulein) decreased meningioma cell survival in vitro. Thus, increased FAS expression in human meningiomas represents a novel therapeutic target for the treatment of unresectable or malignant meningiomas (Haase et al 2010 ;Schaller et al 2007Schaller et al , 2008.…”

Section: Resultsmentioning

confidence: 99%