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

描述（由申请人提供）：患有遗传综合征2型神经纤维瘤病（NF 2）的患者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，导致发病和早期死亡。这些肿瘤是NF 2的定义标准，但也是全球非NF 2患者中最常见的脑肿瘤。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VS，脑膜瘤和NF 2的领先临床和基础科学专家的多机构团队，以测试mTOR（雷帕霉素的哺乳动物靶标）抑制剂RAD 001达到有意义的肿瘤内浓度的假设，并显示mTOR通路抑制的证据以及VS和脑膜瘤患者的生物活性。VS和脑膜瘤缺乏蛋白质Merlin，NF 2基因的基因产物。Merlin缺陷可能导致mTOR分子信号传导途径的异常激活，并且mTOR的抑制可能停止肿瘤生长。因此，我们假设使用mTOR抑制剂（如RAD 001）治疗VS和脑膜瘤患者可能有效。RAD 001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。它最近在一种类似于NF 2的遗传性肿瘤综合征（称为神经性硬化症）中显示出显着的疗效。在其他肿瘤类型中，例如具有Merlin缺失的恶性癌症，由于反馈机制的去抑制，导致AKT的上调，RAD 001的抗肿瘤功效可能受到限制。目前，我们还不知道这种“逃逸”机制是否在体内VS和脑膜瘤中起作用。为了评估RAD 001在体内患者中的肿瘤内活性，同意参与的计划切除VS或脑膜瘤的具有和不具有NF 2的参与者将在手术前服用RAD 001 7天。在手术时，将收集血液和肿瘤组织。将分析血液和肿瘤中的RAD 001水平。我们还将评估药物对肿瘤细胞和局部实质内mTOR通路信号传导和肿瘤生长的影响。本研究的结果将提供重要的生物学数据，为VS和脑膜瘤中mTOR靶向治疗的进一步合理开发提供信息。如果能够在VS和脑膜瘤中实现抑制主要分子药物靶点的RAD 001的生物活性药物浓度，则需要进一步开发基于RAD 001的疗法。如果我们发现分子逃逸机制是可行的，则应探索联合疗法，例如联合mTOR和PI 3 K/AKT阻断。VS和脑膜瘤的有效药物治疗的确定将代表神经肿瘤学的突破，并提高这些肿瘤患者的生活质量和生存率。 公共卫生相关性：前庭神经鞘瘤（VS）和脑膜瘤是最常见的颅内肿瘤，目前大多数患者需要手术和/或放疗，导致严重的急性和长期发病率。实验室数据表明，抑制mTOR信号通路的分子靶向药物RAD 001可能有效治疗VS和脑膜瘤患者。我们将研究需要手术治疗VS或脑膜瘤的患者的手术标本，这些患者同意在手术前立即服用7天的RAD 001。我们预计这项研究的结果将产生有关VS和脑膜瘤患者mTOR途径生物学的关键信息，并使我们能够合理开发和优化针对该人群的分子靶向疗法。

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. PUBLIC HEALTH RELEVANCE: Vestibular schwannomas (VS) and meningiomas are among the most common intracranial tumors, and most patients currently require surgery and/or radiotherapy, resulting in significant acute and long-term morbidity. Laboratory data suggests that RAD001, a molecular targeted drug inhibiting the mTOR signaling pathway, may be effective in the treatment of patients with VS and meningiomas. We will study surgical specimens from patients who require surgery for VS or meningioma and consent to taking a 7-day course of RAD001 immediately prior to surgery. We expect that the results of this study will yield critical information on the mTOR pathway biology in patients VS and meningiomas and will enable us to rationally develop and optimize molecular targeted therapies for this population.