mTORC1 Inhibitors Suppress Meningioma Growth in Mouse Models

Pachow, Doreen; Andrae, Nadine; Kliese, Nadine; Angenstein, Frank; Stork, Oliver; Wilisch‐Neumann, Annette; Kirches, Elmar; Mawrin, Christian

doi:10.1158/1078-0432.ccr-12-1904

Cited by 90 publications

(103 citation statements)

References 27 publications

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“…In contrast to their results, we observed a similar effect in both aggressive and benign tumors (Table 1) [12]. According to Pachow et al, using NF2-shRNA on meningioma cell lines, sensitivity to rapalogs may be dependent on merlin expression level [28], although these observations remain unelucidated on human meningiomas. Temsirolimus (another rapalog) has recently shown an inhibitory effect on the tumoral growth of xenografts in nude mice, obtained after transplantation of IOMM-Lee meningioma cell line [28].…”

Section: Mtor Inhibitors Effect On Meningiomascontrasting

confidence: 90%

“…According to Pachow et al, using NF2-shRNA on meningioma cell lines, sensitivity to rapalogs may be dependent on merlin expression level [28], although these observations remain unelucidated on human meningiomas. Temsirolimus (another rapalog) has recently shown an inhibitory effect on the tumoral growth of xenografts in nude mice, obtained after transplantation of IOMM-Lee meningioma cell line [28]. Altogether, these results highlight the potential therapeutic interest of rapalogs in the tumoral control of meningioma in humans.…”

Section: Mtor Inhibitors Effect On Meningiomasmentioning

confidence: 99%

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Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas

et al. 2015

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Treatment for recurrent and aggressive meningiomas remains an unmet medical need in neuro-oncology, and chemotherapy exhibits limited clinical activity, if any. Merlin expression, encoded by the NF2 gene, is lost in a majority of meningiomas, and merlin is a negative regulator of mTORC1. The sst2 somatostatin receptor, targeted by octreotide, is highly expressed in meningiomas. To investigate new therapeutic strategies, we evaluated the activity of everolimus (mTOR inhibitor), BKM-120 and BEZ-235 (new Pi3K/Akt/mTOR inhibitors), octreotide and a combined treatment (octreotide plus everolimus), on cell proliferation, signaling pathways, and cell cycle proteins, respectively. The in vitro study was conducted on human meningioma primary cells extracted from fresh tumors, allowing the assessment of somatostatin analogs at the concentration levels used in patients. The results were correlated to WHO grades. Further, everolimus decreased cell viability of human meningiomas, but concomitantly, induced Akt activation, reducing the antiproliferative effect of the drug. The new Pi3K inhibitors were not more active than everolimus alone, limiting their clinical relevance. In contrast, a clear cooperative inhibitory effect of octreotide and everolimus was observed on cell proliferation in all tested meningiomas, including WHO grades II-III. Octreotide not only reversed everolimus-induced Akt phosphorylation but also displayed additive and complementary effects with everolimus on downstream proteins involved in translation (4EB-P1), and controlling cell cycle (p27Kip1 and cyclin D1). We have demonstrated a co-operative action between everolimus and octreotide on cell proliferation in human meningiomas, including aggressive ones, establishing the basis for a clinical trial.

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Section: Mtor Inhibitors Effect On Meningiomascontrasting

confidence: 90%

Section: Mtor Inhibitors Effect On Meningiomasmentioning

confidence: 99%

Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas

et al. 2015

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“…A few preclinical trials have been published with regard to meningioma specifically. Pachow et al 56 recently published a study demonstrating significant reductions in meningioma cell growth in mouse models treated with the mTOR inhibitor drugs temsirolimus and everolimus.…”

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confidence: 99%

Recent developments in chemotherapy for meningiomas: a review

Moazzam

Wagle

Zada

2013

FOC

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Object Currently, few medical options exist for refractory and atypical/anaplastic meningiomas. New developments in chemotherapeutic options for meningiomas have been explored over the past decade. The authors review these recent developments, with an emphasis on emerging avenues for therapy, clinical efficacy, and adverse effects. Methods A review of the literature was performed to identify any studies exploring recent medical and chemotherapeutic agents that have been or are currently being tested for meningiomas. Results from included preclinical and human clinical trials were reviewed and summarized. Results Current guidelines recommend only 3 drugs that can be used to treat patients with refractory and highgrade meningiomas: hydroxyurea, interferon-α 2B, and Sandostatin long-acting release. Recent developments in the medical treatment of meningiomas have been made across a variety of pharmacological classes, including cytotoxic agents, hormonal agents, immunomodulators, and targeted agents toward a variety of growth factors and their signaling cascades. Promising avenues of therapy that are being evaluated for efficacy and safety include antagonists of platelet-derived growth factor receptor, epidermal growth factor receptor, vascular endothelial growth factor receptor, and mammalian target of rapamycin. Because malignant transformation in meningiomas is likely to be mediated by numerous processes interacting via a complex matrix of signals, combination therapies affecting multiple molecular targets are currently being explored and hold significant promise as adjuvant therapy options. Conclusions Improved understanding of the molecular mechanisms driving meningioma tumorigenesis and malignant transformation has resulted in the targeted development of more specific agents for chemotherapeutic intervention in patients with nonresectable, aggressive, and malignant meningiomas.

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“…In the animal model, the use of mTOR inhibitors such as temsirolimus and everolimus showed a reduced growth rate in meningioma cells [71]. On the contrary, the application of EGFR inhibitors (gefitinib and erlotinib) did not show a significant benefit in patients with refractory meningiomas [72].…”

Section: Chemotherapymentioning

confidence: 98%

Meningiomas’ Management: An Update of the Literature

Cossu¹,

Messerer²,

Parker³

et al. 2016

Neurooncology - Newer Developments

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Meningiomas are the most common primary intracranial tumors in the adult population [1]. They are generally considered benign lesions but after the 2007 WHO classification, the proportion of atypical meningiomas has steeply increased. Surgery is considered the mainstay of the treatment and a complete resection is considered curative in WHO grade I meningiomas. The role of adjuvant treatments like radiotherapy (stereotactic radiosurgery or conventional external beam irradiation) and chemotherapy in more aggressive cases is still discussed, above all in WHO grade II meningiomas. We would like to expose the most important advances in meningiomas' management in accordance with the recent literature evidences.

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mTORC1 Inhibitors Suppress Meningioma Growth in Mouse Models

Cited by 90 publications

References 27 publications

Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas

Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas

Recent developments in chemotherapy for meningiomas: a review

Meningiomas’ Management: An Update of the Literature

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