Sunitinib targets PDGF-receptor and Flt3 and reduces survival and migration of human meningioma cells

Andrae, Nadine; Kirches, Elmar; Hartig, Roland; Haase, Daniela; Keilhoff, Gerburg; Kalinski, Thomas; Mawrin, Christian

doi:10.1016/j.ejca.2012.01.032

Cited by 48 publications

(39 citation statements)

References 38 publications

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“…After its local delivery from REM, sunitinib could exert both anti-angiogenic and cytotoxic effects. The anti-angiogenic activity is expected to occur at nanomolar concentrations of sunitinib while the cytotoxic activity could occur at micromolar concentrations (Mendel et al, 2003;de Boüard et al, 2007;Andrae et al, 2012). Preclinical studies in rabbit VX2 tumor model are now required to determine whether CE with fast resorbable REM loaded with sunitinib could reduce tumoral angiogenesis and induced tumoral necrosis as reported for non-degradable DC Bead 1 loaded with sunitinib (Bize et al, 2013).…”

Section: Sunitinibmentioning

confidence: 91%

Anti-angiogenic drug delivery from hydrophilic resorbable embolization microspheres: An in vitro study with sunitinib and bevacizumab

Bédouet¹,

Verret²,

Louguet³

et al. 2015

International Journal of Pharmaceutics

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Section: Sunitinibmentioning

confidence: 91%

Anti-angiogenic drug delivery from hydrophilic resorbable embolization microspheres: An in vitro study with sunitinib and bevacizumab

Bédouet¹,

Verret²,

Louguet³

et al. 2015

International Journal of Pharmaceutics

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“…in ovarian carcinoma [17, 53] and peritoneal metastases of colorectal carcinomas [18] targeting αvβ3-integrin or folate receptor α and VEGF-α, respectively. For the development of a similar approach in meningioma surgery, various biomarkers have been suggested, including epithelial membrane antigen (EMA), platelet-derived growth factor beta (PDGF-β), vascular endothelial growth factor A (VEGF-α), and somatostatin receptor type 2 (SSTR-2) [3, 5, 9, 11, 12, 16, 19, 21, 28, 30, 32, 38, 39, 43–45, 48, 52, 56]. However, the suitability of these markers for fluorescence-guided imaging meningioma surgery has not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

SSTR-2 as a potential tumour-specific marker for fluorescence-guided meningioma surgery

et al. 2018

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BackgroundMeningiomas are the most frequently occurring primary intracranial tumours in adults. Surgical removal can only be curative by complete resection; however surgical access can be challenging due to anatomical localization and local invasion of bone and soft tissues. Several intraoperative techniques have been tried to improve surgical resection, including intraoperative fluorescence guided imaging; however, no meningioma-specific (fluorescent) targeting has been developed yet. Here, we aimed to identify the most promising biomarkers for targeted intra-operative fluorescence guided meningioma surgery.MethodsOne hundred forty-eight meningioma specimens representing all meningioma grades were analysed using immunohistochemistry (IHC) on tissue microarrays (TMAs) to determine expression patterns of meningioma biomarkers epithelial membrane antigen (EMA), platelet-derived growth factor β (PDGF-β), vascular endothelial growth factor α (VEGF-α), and somatostatin receptor type 2 (SSTR-2). Subsequently, the most promising biomarker was selected based on TArget Selection Criteria (TASC). Marker expression was examined by IHC in 3D cell culture models generated from freshly resected tumour material.ResultsTMA-IHC showed strongest staining for SSTR-2. All cases were positive, with 51.4% strong/diffuse, 30.4% moderate/diffuse and only 18.2% focal/weak staining patterns. All tested biomarkers showed at least weak positivity in all meningiomas, regardless of WHO grade. TASC analysis showed that SSTR-2 was the most promising target for fluorescence guided imaging, with a total score of 21 (out of 22). SSTR-2 expression was determined on original patient tumours and 3D cultures of three established cultures.ConclusionsSSTR-2 expression was highly sensitive and specific in all 148 meningiomas, regardless of WHO grade. According to TASC analysis, SSTR-2 is the most promising receptor for meningioma targeting. After establishing in vitro meningioma models, SSTR-2 cell membrane expression was confirmed in two of three meningioma cultures as well. This indicates that specific fluorescence in an experimental setting can be performed for the further development of targeted fluorescence guided meningioma surgery and near-infrared fluorescent tracers targeting SSTR-2.

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“…Cells in microtiter plates (2000/well) were treated for 24 hours with the indicated concentrations of temsirolimus (Torisel, Pfizer) or everolimus (RAD001, NOVARTIS) before standard MTT or bromodeoxyuridine (BrdUrd) assays, as described previously (20). In some experiments, treated cells were in addition irradiated with the indicated dosage of X-rays in a Gulmay D3225 machine (Gulmay Inc) and analyzed by an MTT assay 24 hours thereafter.…”

Section: Mtt and Brdurd Assaysmentioning

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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Sunitinib targets PDGF-receptor and Flt3 and reduces survival and migration of human meningioma cells

Cited by 48 publications

References 38 publications

Anti-angiogenic drug delivery from hydrophilic resorbable embolization microspheres: An in vitro study with sunitinib and bevacizumab

Anti-angiogenic drug delivery from hydrophilic resorbable embolization microspheres: An in vitro study with sunitinib and bevacizumab

SSTR-2 as a potential tumour-specific marker for fluorescence-guided meningioma surgery

mTORC1 Inhibitors Suppress Meningioma Growth in Mouse Models

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