Exploration of Activity of RAD001 in vivo in Vestibular Schwannomas and Meningiom

描述(申请人提供)：患有遗传性神经纤维瘤病2型(NF2)的患者会发展为多发性颅内和脊椎肿瘤，包括前庭神经鞘瘤(VS)和脑膜瘤，导致发病率和早期死亡。这些肿瘤是NF2的定义标准，但也是全世界非NF2患者最常见的脑肿瘤之一。目前还没有已知的治疗VS或脑膜瘤的有效药物。这项建议汇集了VS、脑膜瘤和NF2领域领先的临床和基础科学专家组成的多机构团队，以测试mTOR(雷帕霉素的哺乳动物靶标)抑制剂RAD001达到有意义的肿瘤内浓度的假设，并显示mTOR通路抑制以及患者VS和脑膜瘤的生物活性的证据。VS和脑膜瘤缺乏NF2基因的基因产物Merlin蛋白。Merlin缺乏可能导致mTOR分子信号通路的异常激活，抑制mTOR可能阻止肿瘤生长。因此，我们假设mTOR抑制剂，如RAD001，对VS和脑膜瘤患者的治疗可能有效。RAD001是一种耐受性良好的口服药物，具有良好的安全性和抗肿瘤活性，可对抗多种类型的癌症。它最近在一种名为结节性硬化症的类似NF2的基因肿瘤综合征中显示出显着的疗效。在其他肿瘤类型中，如伴有Merlin缺失的恶性肿瘤，RAD001的抗肿瘤效果可能由于反馈机制的解除抑制而受到限制，导致AKT上调。目前，我们不知道这种“逃逸”机制是否在活体VS和脑膜瘤中起作用。为了评估RAD001在体内患者中的肿瘤内活性，计划切除VS或脑膜瘤的患者中，有NF2和没有NF2的参与者同意参与，在手术前7天服用RAD001。手术时，将采集血液和肿瘤组织。血液和肿瘤中的RAD001水平将被分析。我们还将评估该药物对肿瘤细胞和局部实质内mTOR信号通路和肿瘤生长的影响。这项研究的结果将提供重要的生物学数据，为进一步合理开发mTOR靶向治疗VS和脑膜瘤提供信息。如果在VS和脑膜瘤中能够达到抑制主要分子药物靶点的RAD001的生物活性药物浓度，那么基于RAD001的治疗方法的进一步发展是有必要的。如果我们发现分子逃逸机制是可行的，应该探索联合治疗，如联合mTOR和PI3K/AKT阻断。VS和脑膜瘤的有效药物治疗的确定将代表着神经肿瘤学的突破，并提高这些肿瘤患者的生活质量和生存。

DESCRIPTION (provided by applicant): Patients with the genetic syndrome Neurofibromatosis type 2 (NF2) develop multiple intracranial and spinal tumors, including vestibular schwannomas (VS) and meningioma that lead to morbidity and early mortality. These tumors are the defining criteria for NF2, but are also among the most common brain tumors worldwide in non-NF2 patients. There are no known effective medical therapies for either VS or meningiomas. This proposal brings together a multi-institutional team of leading clinical and basic science experts in VS, meningiomas and NF2 to test the hypothesis that the mTOR (mammalian target of rapamycin) inhibitor RAD001 reaches meaningful intratumoral concentrations and shows evidence of mTOR pathway inhibition as well as biological activity in VS and meningioma in patients. VS and meningiomas are deficient in the protein Merlin, the gene product of the NF2 gene. Merlin deficiency may result in abnormal activation of the mTOR molecular signaling pathway and that inhibition of mTOR may stop tumor growth. We therefore hypothesize that treatment with mTOR inhibitors, such as RAD001, may be effective in the treatment of patients with VS and meningiomas. RAD001 is a well-tolerated oral drug with a favorable safety profile and anti-tumor activity against several types of cancer. It has recently shown remarkable efficacy in a genetic tumor syndrome similar to NF2 called Tuberous Sclerosis. In other tumor types, such as malignant cancers with Merlin loss, the anti-tumor efficacy of RAD001 may be limited due to disinhibition of a feedback mechanism, leading to the upregulation of AKT. At the present time, we do not know if this "escape" mechanism is operational in VS and meningiomas in vivo. To assess the intratumoral activity of RAD001 in patients in vivo, participants with and without NF2 scheduled for resection of a VS or meningioma who agree to participate, will take RAD001 for 7 days preceding surgery. At the time of surgery, blood and tumor tissue will be collected. RAD001 levels in the blood and tumor will be analyzed. We will also assess the effects of the drug on mTOR pathway signaling and tumor growth within the tumor cells and local parenchyma. The results of this study will provide important biological data that will inform further, rational development of mTOR-targeted therapies in VS and meningiomas. If biologically active drug concentrations of RAD001 that inhibit the primary molecular drug target can be achieved in VS and meningiomas, further development of RAD001-based therapies is warranted. If we find molecular escape mechanisms to be operational, combination therapies, such as combined mTOR and PI3K/AKT blockade should be explored. The identification of an effective medical therapy for VS and meningiomas would represent a breakthrough in neuro-oncology and enhance the quality of life and survival in patients with these tumors.