TR-13EFFECTS OF EVEROLIMUS ON MENINGIOMA GROWTH IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2
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PROVIDER: S-EPMC4482947 | biostudies-literature | 2015 Apr
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND: Vestibular schwannomas (VS) and meningiomas are associated with biallelic loss of NF2, and may arise sporadically or in the context of the tumor predisposition syndrome neurofibromatosis type 2. Loss of NF2 activates the mammalian target of rapamycin (mTOR) pathway, and published in vitro and in vivo data indicate that mTOR inhibition may be effective in the treatment of NF2-deficient VS and meningiomas. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with anti-tumor activity in a variety of tumors. METHODS: We conducted a retrospective review of patients with NF2 and progressive vestibular schwannomas treated with everolimus on our prospective phase II clinical trial (ClinicalTrials.gov NCT01419639). Everolimus was administered at a daily dose of 10 mg in continuous 28-day courses for up to 12 courses. In this retrospective study, we included patients with at least one volumetrically measurable meningioma (>0.5 cc) who received at least six 28-day courses of therapy. Tumor response was assessed with brain MRI every three months using three-dimensional volumetric analysis. RESULTS: Three patients met criteria and had 10 evaluable meningiomas, with a total combined volume of 11.84 cc at baseline (median 1.20 cc, range 0.53–3.00 cc). Median time on therapy was 9 months (range 6–12 months). Total combined meningioma volume remained stable during treatment (-1.8%). Correspondingly, none of the individual tumors analyzed met criteria for volumetric response or progression during the treatment period (range -10% to +9.4%). CONCLUSIONS: Neither objective response nor progression was appreciated in meningiomas patients during a median treatment duration of 6 months. Further clinical studies will be required to determine whether everolimus affects meningioma growth velocity in patients with NF2. To better understand pharmacologic mTOR signaling pathway modulation in human VS and meningiomas in vivo, we are currently conducting a multi-center pharmacodynamic/pharmacokinetic (“phase 0”) study with everolimus (NCT01880749).
| S-EPMC4217809 | biostudies-literature
Project description:IntroductionEpidermal growth factor receptors EGFR and ErbB2 are overexpressed in schwannomas and meningiomas. Preclinical and clinical data indicate that lapatinib, an EGFR/ErbB2 inhibitor, has antitumor activity against vestibular schwannomas in neurofibromatosis type 2 (NF2) patients. Its antitumor activity against meningiomas, however, is unknown.MethodsWe conducted a retrospective review of patients with NF2 and progressive vestibular schwannomas treated on a phase 2 clinical trial with lapatinib (NCT00973739). We included patients with at least one volumetrically measurable meningioma (> 0.5 cm3) who received at least five 28-day courses of treatment. Patients received lapatinib 1500 mg daily. Meningioma response was assessed using 3-dimensional MRI volumetrics. Progressive meningioma growth and response were defined as + 20 and - 20% change in tumor volume from baseline, respectively. Off-treatment was defined as any period > 5 months without lapatinib.ResultsEight patients (ages: 20-58 years) who met criteria had 17 evaluable meningiomas with a combined volume of 61.35 cc at baseline, 61.17 cc during treatment, and 108.86 cc (+ 77.44% change) off-treatment, p = 0.0033. Median time on-treatment and off-treatment was 15.5 and 16.7 months, respectively. On-treatment mean and median annualized growth rates were 10.67 and 1.32%, respectively. Off-treatment mean and median annualized growth rates were 20.05 and 10.42%, respectively. The best volumetric response was - 26.1% after 23 months on lapatinib. Two tumors increased > 20% volumetrically on-treatment, compared to eight tumors off-treatment.ConclusionsThese data suggest that lapatinib may have growth-inhibitory effects on meningiomas in NF2 patients, and support prospective studies of lapatinib for NF2 patients with progressive meningiomas.
| S-EPMC6126973 | biostudies-literature
Project description: Not available
| S-EPMC9634461 | biostudies-literature
Project description:BackgroundMeningiomas are usually associated with neurofibromatosis type 2 (NF-2), while gliomas are usually associated with neurofibromatosis type 1 (NF-1). NF-1 is an autosomal dominant genetic disorder associated with skin manifestations, bone conditions, and different types of benign and malignant tumors. Grade 3 anaplastic meningiomas are rare tumors with a poor prognosis. Systemic treatments in grade 3 meningiomas are experimental, with some reports suggestive of minimal clinical benefits. They are used occasionally for recurrent cases with no surgical or radiotherapy roles. In our case, we will focus the discussion on grade 3 anaplastic meningioma in a patient with NF-1, using chemotherapy for this aggressive, recurrent tumor. To our knowledge, this is the first case of NF-1 associated with malignant anaplastic meningioma in English literature.Case descriptionIn this case report, we present a 25-year-old left-handed female patient who fits the diagnostic criteria for NF-1. She presented with focal seizure and was diagnosed with grade 3 anaplastic meningioma, a highly aggressive tumor. She experienced a rapid recurrence after her initial surgery and eventually received multiple lines of treatments, including radiation and chemotherapy [temozolomide (TMZ)].ConclusionsSystemic therapy in grade 3 meningiomas is still experimental and may have a slight clinical benefit. As a result, further prospective, multicentric studies are needed to ascertain these outcomes. Patients should be included in prospective trials because of the poor prognosis and aggressive nature of grade 3 meningiomas. In addition, discovering specific molecular biomarkers will allow us to suggest an individualized treatment. This case suggests that the differential diagnosis of a mass in a patient with NF-1 should include tumors known to be associated with the syndrome as well as sporadic, unrelated neoplasms.
| S-EPMC9634465 | biostudies-literature
Project description:Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. Meningiomas are a common primary brain tumor; many NF2 patients suffer from multiple meningiomas. In NF2, patients have mutations in the NF2 gene, specifically with loss of function in a tumor-suppressor protein that has a number of synonymous names, including: Merlin, Neurofibromin 2, and schwannomin. Merlin is a 70 kDa protein that has 10 different isoforms. The Hippo Tumor Suppressor pathway is regulated upstream by Merlin. This pathway is critical in regulating cell proliferation and apoptosis, characteristics that are important for tumor progression. Mutations of the NF2 gene are strongly associated with NF2 diagnosis, leading to benign proliferative conditions such as vestibular schwannomas and meningiomas. Unfortunately, even though these tumors are benign, they are associated with significant morbidity and the potential for early mortality. In this review, we aim to encompass meningiomas and vestibular schwannomas as they pertain to NF2 by assessing molecular genetics, common tumor types, and tumor pathogenesis.
| S-EPMC7828193 | biostudies-literature
Project description:Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of patients with neurofibromatosis type 2 (NF2) with vestibular schwannoma. To assess the pharmacokinetics, pharmacodynamics, and potential mechanisms of treatment resistance, we performed a presurgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for vestibular schwannoma or meningiomas. Eligible patients with meningioma or vestibular schwannoma requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately before and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and postoperative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/mL and 9.4 ng/mL, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range, 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared with control tissues from untreated patients (P = 0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited antitumor effect of everolimus observed in clinical studies for patients with NF2 and will inform the design of future preclinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.
| S-EPMC8419097 | biostudies-literature
Project description:Meningioma is the second most frequent tumor in patients with neurofibromatosis type 2 (NF2). The presence of meningioma is believed to be a negative prognostic marker in these patients. However, the molecular mechanisms involved in the tumorigenesis of NF2-associated meningioma are not well characterized. Epigenetic regulation, including microRNAs (miRNAs), may be involved in the development of different tumor types in patients with NF2. The objective of this study is to explore the different characteristics of serum miRNA expression depending on the presence or absence of meningioma in patients with NF2. Nine patients with NF2 who were treated at the Department of Neurosurgery, Hiroshima University Hospital, were included. Total RNA (including small RNAs) was extracted from serum samples for the preparation of a small RNA library for next-generation sequencing analysis. Differentially expressed miRNAs (DEMs) were analyzed using the DESeq2 package to compare the characteristic miRNA expression profiles of patients with and without meningioma. In small RNA sequencing analysis, out of a total of 1,879 miRNAs registered in the database, the expressions of 657 miRNAs were observed. In DEM analysis, the expressions of four miRNAs, namely, hsa-miR-664b, hsa-miR-7706, hsa-miR-590, and hsa-miR-6513, were downregulated in patients with NF2 with meningioma compared with patients with NF2 without meningioma. Hsa-miR-193a was identified as the only upregulated miRNA in patients with NF2 with meningioma. In conclusion, we identified different circulating miRNA expression characteristics depending on the presence or absence of meningioma in patients with NF2.
| S-EPMC10992986 | biostudies-literature
Project description:BackgroundActivation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers.MethodsWe conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m(2)/day (children <18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as ≥15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients.ResultsNone of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules.ConclusionEverolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic ("phase 0") study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors.
| S-EPMC3895376 | biostudies-literature
Project description:BackgroundNeurofibromatosis type 2 (NF2) is a rare autosomal dominant genetic disorder, resulting in a variety of neural tumors, with bilateral vestibular schwannomas as the most frequent manifestation. Recently, merlin, the NF2 tumor suppressor, has been identified as a novel negative regulator of mammalian target of rapamycin complex 1 (mTORC1); functional loss of merlin was shown to result in elevated mTORC1 signaling in NF2-related tumors. Thus, mTORC1 pathway inhibition may be a useful targeted therapeutic approach.MethodsWe studied in vitro cell models, cohorts of mice allografted with Nf2(-/-) Schwann cells, and a genetically modified mouse model of NF2 schwannoma in order to evaluate the efficacy of the proposed targeted therapy for NF2.ResultsWe found that treatment with the mTORC1 inhibitor rapamycin reduced the severity of NF2-related Schwann cell tumorigenesis without significant toxicity. Consistent with these results, in an NF2 patient with growing vestibular schwannomas, the rapalog sirolimus induced tumor growth arrest.ConclusionsTaken together, these results constitute definitive evidence that justifies proceeding with clinical trials using mTORC1-targeted agents in selected patients with NF2 and in patients with NF2-related sporadic tumors.
| S-EPMC3956353 | biostudies-literature
Project description:Neurofibromatosis type 1 (NF1), or von Recklinghausen disease, is an autosomal dominant disease that presents with various symptoms, including café-au-lait spots and neurofibromas. NF1 patients occasionally suffer from renal artery vasculopathy, which impairs renal function, while results of a previous report suggested that male NF1 patients have a low creatinine level in peripheral blood. The assessment of renal function in NF1 patients remains inadequate. In this study, renal function in NF1 was assessed. We recruited 308 patients consisting of 149 NF1 patients (77 males and 72 females) and 159 control patients (102 males and 57 females). Creatinine, blood urea nitrogen and haemoglobin A1c in peripheral blood as well as protein, occult blood and sugar in urine were examined. In addition, the estimated glomerular filtration rate was calculated. The mean age and body mass index did not differ significantly between the NF1 patients and controls for both sexes. For both sexes, i) the mean creatinine value was significantly lower in the NF1 patients than in the controls; ii) the mean blood urea nitrogen value did not differ significantly between the NF1 patients and controls; iii) the mean blood urea nitrogen-to-creatinine ratio was significantly higher in the NF1 patients than in the controls; iv) the mean estimated glomerular filtration rate was significantly higher in the NF1 patients than in the controls; and v) the mean haemoglobin A1c value was significantly lower in the NF1 patients than in the controls. In conclusion, NF1 patients may have improved renal function. The clinical significances should be further examined.
| S-EPMC9168021 | biostudies-literature