mTORC1 inhibition delays growth of neurofibromatosis type 2 schwannoma

Giovannini, Marco; Bonne, N.-X.; Vitte, Jérémie; Chareyre, Fabrice; Tanaka, Karo; Adams, Rocky; Fisher, Laurel M.; Valeyrie‐Allanore, Laurence; Wolkenstein, Pierre; Goutagny, Stéphane; Kalamaridès, Michel

doi:10.1093/neuonc/not242

Cited by 68 publications

(60 citation statements)

References 45 publications

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“…4) [24]. This is in line with our observation in schwannoma mouse model, where a small increase in phospho-AKT seen under rapamycin treatment normalized after treatment discontinuation [15]. The three VS exhibited marked elevated S6 phosphorylation as observed in our mouse schwannoma model, where tumor growth inhibition was dependent on continuous exposure to rapamycin, with S6 phosphorylation re-expression after rapamycin withdrawal.…”

Section: Tumor Tissue Biomarker Evaluationsupporting

confidence: 89%

“…3). As previously reported in an index NF2 patient treated with rapamycin [15], a concentrationdependent response was observed. Everolimus blood trough levels were higher in stable patients than in progressive patients (median 22.7 lg/mL (IQR 16.5-30.2) versus 10.6 (IQR 9.7-15.5), P = 0.03 Mann-Whitney test).…”

Section: Radiological Evaluation Of Drug Activitysupporting

confidence: 84%

“…After treatment discontinuation, two of four patients experienced hearing decline (-13 dB, see Online Resource 3), associated with tumor growth. Re-introduction of everolimus was associated with a restoration of PTA to previous levels (15,32,6, and 27 dB at M24).…”

Section: Other Per Protocol Evaluations Of Drug Effectsmentioning

confidence: 82%

“…In a previous study, we have shown that mTORC1 inhibition by rapamycin reduced the severity of NF2-related Schwann cell tumorigenesis in several relevant in vitro and in vivo models without significant toxicity [15]. Concomitant with these preclinical studies, we administered rapamycin to an index patient with growing VS over a prolonged period of time resulting in a clinically meaningful delay to progression.…”

Section: Introductionmentioning

confidence: 99%

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Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas

et al. 2015

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Neurofibromatosis type 2 (NF2) is a genetic disorder with bilateral vestibular schwannomas (VS) as the most frequent manifestation. Merlin, the NF2 tumor suppressor, was identified as a negative regulator of mammalian target of rapamycin complex 1. Pre-clinical data in mice showed that mTORC1 inhibition delayed growth of NF2-schwannomas. We conducted a prospective singleinstitution open-label phase II study to evaluate the effects of everolimus in ten NF2 patients with progressive VS. Drug activity was monitored every 3 months. Everolimus was administered orally for 12 months and, if the decrease in tumor volume was [20 % from baseline, treatment was continued for 12 additional months. Other patients stopped when completed 12 months of everolimus but were allowed to resume treatment when VS volume was [20 % during 1 year follow-up. Nine patients were evaluable. Safety was evaluated using CTCAE 3.0 criteria. After 12 months of everolimus, no reduction in volume C20 % was observed. Four patients had progressive disease, and five patients had stable disease with a median annual growth rate decreasing from 67 %/year before treatment to 0.5 %/year during treatment. In these patients, tumor growth resumed within 3-6 months after treatment discontinuation. Everolimus was then reintroduced and VS decreased by a median 6.8 % at 24 months. Time to tumor progression increased threefold from 4.2 months before treatment to [ 12 months. Hearing was stable under treatment. The safety of everolimus was manageable.To the memory of Beatrice Larroque, who died accidentally as this paper was written.Electronic supplementary material The online version of this article

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Section: Tumor Tissue Biomarker Evaluationsupporting

confidence: 89%

Section: Radiological Evaluation Of Drug Activitysupporting

confidence: 84%

Section: Other Per Protocol Evaluations Of Drug Effectsmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas

et al. 2015

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“…The volume calculation algorithm in OsiriX was used to obtain a threedimensional tumor volumetric measurement (mm 3 ) complex region, using the SC4-9 cell line. SC4-9 has become a standard model in NF2 research since it recapitulates signalling network signatures of human and mouse NF2 schwannomas [19,21,25,26], with high grafting efficiency when orthotopically injected into the sciatic nerves of immunodeficient NU/NU mice [34]. We found that the microsurgical approach successfully targeted the anatomic location where human VS predominantly arise and tumor development could be monitored by in vivo imaging.…”

Section: Discussionmentioning

confidence: 88%