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

描述（由申请人提供）：遗传综合征2型神经纤维瘤病（NF2）患者可发生多发性颅内和脊柱肿瘤，包括前庭神经鞘瘤（VS）和脑膜瘤，可导致发病率和早期死亡。这些肿瘤是NF2的定义标准，但也是世界上非NF2患者中最常见的脑肿瘤之一。目前还没有已知的有效的药物治疗VS或脑膜瘤。该提案汇集了一个由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，以验证mTOR（哺乳动物雷帕霉素靶点）抑制剂RAD001达到有意义的瘤内浓度，并在VS和脑膜瘤患者中显示mTOR途径抑制和生物活性的证据。VS和脑膜瘤缺乏蛋白Merlin，这是NF2基因的基因产物。Merlin缺乏可导致mTOR分子信号通路异常激活，抑制mTOR可阻止肿瘤生长。因此，我们假设使用mTOR抑制剂（如RAD001）治疗VS和脑膜瘤患者可能有效。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，可治疗多种类型的癌症。它最近在一种类似于NF2的基因肿瘤综合征结节性硬化症中显示出显著的疗效。在其他肿瘤类型中，如梅林基因缺失的恶性肿瘤，RAD001的抗肿瘤作用可能受到限制，这可能是由于一种反馈机制的去抑制，导致AKT上调。目前，我们还不知道这种“逃逸”机制是否在VS和脑膜瘤体内起作用。为了评估RAD001在患者体内的肿瘤内活性，有或没有NF2计划切除VS或脑膜瘤的参与者同意参与，将在手术前7天服用RAD001。在手术时，血液和肿瘤组织将被收集。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通路信号和肿瘤生长的影响。这项研究的结果将提供重要的生物学数据，为进一步合理地开发针对VS和脑膜瘤的mtor靶向治疗提供信息。如果能够在VS和脑膜瘤中实现抑制主要分子药物靶点的RAD001生物活性药物浓度，则需要进一步开发基于RAD001的治疗方法。如果我们发现分子逃逸机制是可行的，就应该探索联合治疗，如mTOR联合阻断PI3K/AKT。发现一种有效治疗VS和脑膜瘤的药物将代表神经肿瘤学的一个突破，并提高这些肿瘤患者的生活质量和生存率。

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.