sirolimus and Neurofibromatosis-2

Activation 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.. We 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.. None 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.. Everolimus 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.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Disease Progression; Everolimus; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Neoplasm Staging; Neurofibromatosis 2; Neuroma, Acoustic; Prognosis; Prospective Studies; Sirolimus; Survival Rate; Young Adult

Topics: Adolescent; Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Child; Child, Preschool; Drug Synergism; Erlotinib Hydrochloride; Female; Humans; Indoles; Male; Molecular Targeted Therapy; Neurofibromatosis 2; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases; Treatment Outcome; Valproic Acid; Vascular Endothelial Growth Factor A; Young Adult

Neurofibromatosis 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.. We 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.. We 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.. Taken 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.

Topics: Animals; Apoptosis; Blotting, Western; Cell Proliferation; Cell Size; Enzyme-Linked Immunosorbent Assay; Humans; Immunoenzyme Techniques; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Nude; Mice, Transgenic; Multiprotein Complexes; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured