Phase II trial of mTORC1/mTORC2 inhibitor AZD2014 for sporadic meningioma

脑膜瘤是一种起源于脑膜上皮蛛网膜细胞的肿瘤，是最常见的肿瘤。 成人的原发颅内肿瘤。WHO II级(非典型)或WHO III级(间变性或恶性)肿瘤 表现出更具侵略性的临床行为，增长迅速，复发率增加。海流 脑膜瘤的标准护理是最大限度安全的手术切除，并保留辅助放射治疗 进行性肿瘤或具有侵袭性特征的肿瘤(例如，世卫组织II级或III级)。进展中的脑膜瘤 尽管手术和放射治疗会导致很高的发病率。目前还没有对患者有效的化疗方法。 因此，对于侵袭性脑膜瘤，迫切需要有效的非侵入性治疗。最常见的 散发性脑膜瘤的基因改变是双等位基因NF2基因失活，在50-60%的肿瘤中。我们早些时候 研究证实，NF2蛋白Merlin是mTORC1信号的一种新的负调控因子，从而导致 变构mTORC1抑制剂雷帕霉素类似物RAD001/everolimus治疗NF2和 脑膜瘤患者。到目前为止，临床结果似乎显示出细胞抑制作用，这与 我们对雷帕霉素的体外试验结果。MTOR是一种进化上保守的丝氨酸/苏氨酸蛋白激酶，调节细胞 通过两个不同的功能复合体mTORC1和mTORC2进行生长、增殖和存活。在我们的 最近的研究，我们检测到依赖mTORC2的AGC激酶SGK1(血清和 原代人类脑膜瘤细胞中的糖皮质激素调节蛋白1)，同时伴有和不伴有NF2缺失。这些数据 与SGK1转录表达和SGK1蛋白表达上调一致 我们在人类脑膜瘤中观察到。这些观察结果使我们测试了选择性的双重mTORC1/mTORC2 抑制剂AZD2014，由阿斯利康提供，用于原代人脑膜瘤细胞系。我们的数据令人信服 表明人脑膜瘤细胞中依赖mTORC2的SGK1的激活对AZD2014敏感，但 对雷帕霉素不敏感。AZD2014对原代脑膜瘤细胞的体外治疗作用 NF2的表达，导致细胞增殖抑制，比雷帕霉素更有效。此外，不同于 雷帕霉素、AZD2014不能激活PI3K/Akt/SGK1等生存通路。在这 在该提案中，研究人员与阿斯利康合作，提议在患者身上测试AZD2014的效果 有复发或进展的WHO II级和III级脑膜瘤。这将是一个单臂、多中心、开放的 LABEL，II期研究，评估AZD2014在30例复发患者中的有效性、安全性和耐受性 手术切除加放疗后的II-III级脑膜瘤。这项研究的主要目标是估计 队列患者的6个月无进展生存期。此外，详细的分子和免疫组织化学 将进行分析，以确定脑膜瘤亚组是否对AZD2014有更好的反应。这 研究应该坚定地确定AZD2014是否是未来更大规模随机试验的重要候选药物 脑膜瘤试验。

Meningiomas are tumors that arise from the meningothelial arachnoid cap cells, and are the most common primary intracranial tumor in adults. WHO grade II (atypical) or WHO grade III (anaplastic or malignant) tumors display more aggressive clinical behavior with rapid growth and increased recurrence rates. The current standard of care for meningioma is maximal safe surgical resection with adjuvant radiation reserved for progressive tumors or those with aggressive features (e.g., WHO grades II or III). Meningiomas that progress despite surgery and radiation cause high morbidity. There is no proven effective chemotherapy for patients with aggressive meningiomas therefore, effective non-invasive therapies are much needed. The most common genetic alteration in sporadic meningiomas is bi-allelic NF2 gene inactivation in 50-60% of tumors. Our earlier studies established the NF2 protein merlin as a novel negative regulator of mTORC1 signaling, which led to clinical trials with the allosteric mTORC1 inhibitor rapamycin analog, RAD001/everolimus for NF2 and meningioma patients. The clinical outcome thus far appears to show cytostatic effects, which is consistent with our in vitro results with rapamycin. mTOR is an evolutionarily conserved Ser/Thr kinase that regulates cell growth, proliferation and survival through two distinct functional complexes, mTORC1 and mTORC2. In our recent studies, we have detected specific activation of the mTORC2-dependent AGC kinase SGK1 (serum and glucocorticoid-regulated kinase 1) in primary human meningioma cells with and without NF2 loss. These data are consistent with the elevated SGK1 transcriptional expression and elevated SGK1 protein expression that we observe in human meningiomas. These observations led us to test the selective dual mTORC1/mTORC2 inhibitor AZD2014, provided by AstraZeneca, in primary human meningioma cell lines. Our data convincingly show that activation of mTORC2-dependent SGK1 in human meningioma cells is sensitive to AZD2014, but insensitive to rapamycin. AZD2014 treatment of primary meningioma cells in vitro, whether NF2-deficient or NF2-expressing, leads to decreased cell proliferation with greater efficacy than rapamycin. Further, unlike rapamycin, AZD2014 does not cause activation of prosurvival pathway such as PI3K/Akt/SGK1. In this proposal, the investigators, in partnership with AstraZeneca, propose to test the effect of AZD2014 in patients with recurrent or progressive WHO grade II and III meningiomas. This will be a single-arm, multicenter, open label, phase II study to evaluate the efficacy, safety, and tolerability of AZD2014 in 30 patients with recurrent grade II-III meningioma after surgical resection and radiation. The primary objective of the study is to estimate 6-month progression-free survival for the cohort. Further, detailed molecular and immunohistochemistry analyses will be undertaken to define whether subgroups of meningiomas respond better to AZD2014. This study should firmly establish whether AZD2014 is an important candidate drug for future larger randomized meningioma trials.