Dataset Information

Development of drug treatments for neurofibromatosis type 2-associated vestibular schwannoma.

ABSTRACT: To review the discoveries in molecular pathophysiology contributing to the development of neurofibromatosis type 2 (NF2)-associated vestibular schwannomas and the recent experiences with drug therapies for these tumors. The review includes discussion of diagnostic criteria for NF2, populations to clinically consider for drug therapy and drug targets currently under consideration for NF2.Increased insight into the complex pathways that underlie both the genetic syndrome of NF2 and the specific pathogenesis of vestibular schwannomas has highlighted multiple potential therapeutic targets. These discoveries have been translated into clinical trials with some early promising results. Inhibition of angiogenesis as well as regulation of mammalian target of rapamycin and the epidermal growth factor receptor family of receptors are the focus of current clinical investigations.Although a great deal of work is ongoing to understand the multiple effects of the lack of the regulating protein Merlin on tumorgenesis in patients with NF2, advances are ongoing with clinical therapeutics. There is cause for enthusiasm based on recent results with antiangiogenesis therapy in select patients with NF2 and progressive vestibular schwannomas; however, awareness of the notable risks and limitations of therapies currently in development is required.

SUBMITTER: Blakeley J

PROVIDER: S-EPMC4778430 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Development of drug treatments for neurofibromatosis type 2-associated vestibular schwannoma.

Blakeley Jaishri J

Current opinion in otolaryngology & head and neck surgery 20121001 5

<h4>Purpose of review</h4>To review the discoveries in molecular pathophysiology contributing to the development of neurofibromatosis type 2 (NF2)-associated vestibular schwannomas and the recent experiences with drug therapies for these tumors. The review includes discussion of diagnostic criteria for NF2, populations to clinically consider for drug therapy and drug targets currently under consideration for NF2.<h4>Recent findings</h4>Increased insight into the complex pathways that underlie bo ...[more]

PMID: 22931905

Similar Datasets

Project description:ObjectiveVestibular schwannomas (VSs) are benign nerve sheath tumors that result from mutation in the tumor suppressor gene NF2, with functional loss of the protein merlin. The authors have previously shown that c-Jun N-terminal kinase (JNK) is constitutively active in human VS cells and plays a central role in their survival by suppressing accumulation of mitochondrial superoxides, implicating JNK inhibitors as a potential systemic treatment for VS. Thus, the authors hypothesized that the adenosine 5'-triphosphate-competitive JNK inhibitor AS602801 would demonstrate antitumor activity in multiple VS models.MethodsTreatment with AS602801 was tested in primary human VS cultures, human VS xenografts, and a genetic mouse model of schwannoma (Postn-Cre;Nf2flox/flox). Primary human VS cell cultures were established from freshly obtained surgical tumor specimens; treatment group media was enriched with AS602801. VS xenograft tumors were established in male athymic nude mice from freshly collected human tumor. Four weeks postimplantation, a pretreatment MRI scan was obtained, followed by 65 days of AS602801 (n = 18) or vehicle control (n = 19) treatment. Posttreatment MRI scans were used to measure final tumor volume. Tumors were then harvested. Finally, Postn-Cre;Nf2flox/flox mice were treated with AS602801 (n = 10) or a vehicle (n = 13) for 65 days. Posttreatment auditory brainstem responses were obtained. Dorsal root ganglia from Postn-Cre;Nf2flox/flox mice were then harvested. In all models, schwannoma identity was confirmed with anti-S100 staining, cell proliferation was measured with the EdU assay, and cell death was measured with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. All protocols were approved by the local institutional review board and Institutional Animal Care and Use Committees.ResultsTreatment with AS602801 decreased cell proliferation and increased apoptosis in primary human VS cultures. The systemic administration of AS602801 in mice with human VS xenografts reduced tumor volume and cell proliferation. Last, the AS602801-treated Postn-Cre;Nf2flox/flox mice demonstrated decreased cell proliferation in glial cells in the dorsal root ganglia. However, AS602801 did not significantly delay hearing loss in Postn-Cre;Nf2flox/flox mice up to 3 months posttreatment.ConclusionsThe data suggest that JNK inhibition with AS602801 suppresses growth of sporadic and neurofibromatosis type 2-associated VSs. As such, AS602801 is a potential systemic therapy for VS and warrants further investigation.

Project description:PURPOSE:Bevacizumab treatment at 7.5 mg/kg every 3 weeks results in improved hearing in approximately 35%-40% of patients with neurofibromatosis type 2 (NF2) and progressive vestibular schwannomas (VSs). However, the optimal dose is unknown. In this multicenter phase II and biomarker study, we evaluated the efficacy and safety of high-dose bevacizumab in pediatric and adult patients with NF2 with progressive VS. PATIENTS AND METHODS:Bevacizumab was given for 6 months at 10 mg/kg every 2 weeks, followed by 18 months at 5 mg/kg every 3 weeks. The primary end point was hearing response defined by word recognition score (WRS) at 6 months. Secondary end points included toxicity, radiographic response, quality of life (QOL), and plasma biomarkers. RESULTS:Twenty-two participants with NF2 (median age, 23 years) with progressive hearing loss in the target ear (median baseline WRS, 53%) were enrolled. Nine (41%) of 22 participants achieved a hearing response at 6 months (1 of 7 children and 8 of 15 adults; P = .08). Radiographic response was seen in 7 (32%) of 22 patients with VS at 6 months (7 of 15 adults and 0 of 7 children; P = .05). Common mild to moderate adverse events included hypertension, fatigue, headache, and irregular menstruation. Improvement in NF2-related QOL and reduction in tinnitus-related distress were reported in 30% and 60% of participants, respectively. Paradoxically, high-dose bevacizumab treatment was not associated with a significant decrease in free vascular endothelial growth factor but was associated with increased carbonic anhydrase IX, hepatocyte growth factor, placental growth factor, stromal cell-derived factor 1α, and basic fibroblast growth factor concentrations in plasma. CONCLUSION:High-dose bevacizumab seems to be no more effective than standard-dose bevacizumab for treatment of patients with NF2 with hearing loss. In contrast to adults, pediatric participants did not experience tumor shrinkage. However, adult and pediatric participants reported similar improvement in QOL during induction. Novel approaches using bevacizumab should be considered for children with NF2.

Dataset Information

Development of drug treatments for neurofibromatosis type 2-associated vestibular schwannoma.

Publications

Development of drug treatments for neurofibromatosis type 2-associated vestibular schwannoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets