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

mTORC1/mTORC2抑制剂AZD2014治疗散发性脑膜瘤的II期试验

• 批准号: 9176394
• 负责人: Scott R Plotkin
• 金额: $ 40.04万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-10 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176394
• 关键词: AKT1 gene; Adjuvant; Adult; Advanced Malignant Neoplasm; Agreement; Arachnoid mater; Behavior; Biological Assay; Brain Neoplasms; CCI-779; Cell Line; Cell Proliferation; Cell Survival; Cells; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cytostatics; Data; Disclosure; Enrollment; Excision; FRAP1 gene; Future; Gene Silencing; Genes; Genetic study; Grant; Human; Immunohistochemistry; In Vitro; Intracranial Neoplasms; Malignant Neoplasms; Molecular; Morbidity - disease rate; Mutation; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2; Null Lymphocytes; Operative Surgical Procedures; Other Genetics; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I/II Trial; Phosphotransferases; Pre-Clinical Model; Progression-Free Survivals; Public Health; Radiation; Radiosurgery; Randomized; Reading; Recurrence; Reporting; Research Personnel; Resected; SDZ RAD; Safety; Salvage Therapy; Sgk protein; Signal Pathway; Signal Transduction; Sirolimus; Subgroup; Techniques; Testing; Toxic effect; Tumor Tissue; United States; United States National Institutes of Health; Work; arm; cell growth; chemotherapy; cohort; drug candidate; efficacy testing; experience; genetic analysis; genome editing; inhibitor/antagonist; meningioma; novel; open label; phase 2 study; phase II trial; protein expression; randomized trial; rapid growth; response; small hairpin RNA; smoothened signaling pathway; standard of care; tumor; tumor registry

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.

脑膜瘤是由脑膜炎蛛网膜帽细胞引起的肿瘤，是最常见的 成人的原发性颅内肿瘤。 WHO II级（非典型）或WHO III级（肿瘤或恶性）肿瘤 显示出更具侵略性的临床行为，并快速增长和复发率提高。电流 脑膜瘤的护理标准是最大的安全外科手术切除，辅助辐射保留给 进行性肿瘤或具有侵略性特征的肿瘤（例如，II级或III年）。脑膜瘤的进展 尽管手术和辐射导致高发病率。没有证明患者的有效化疗 因此，使用侵略性的脑膜瘤，急需有效的非侵入性疗法。最常见的 偶发性脑膜瘤的遗传改变是50-60％的肿瘤中的Bi-calilleic NF2基因失活。我们的早期 研究确定了NF2蛋白Merlin作为MTORC1信号的新型负调节剂，这导致了 使用变构MTORC1抑制剂雷帕霉素类似物的临床试验，rad001/everolimus for 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 我们用雷帕霉素的体外结果。 MTOR是一种进化保守的Ser/THR激酶，可调节细胞 通过两个不同的功能复合物MTORC1和MTORC2的生长，增殖和存活。在我们的 最近的研究，我们检测到MTORC2依赖性AGC激酶SGK1的特异性激活（血清和血清和 糖皮质激素调节的激酶1）在有或没有NF2损失的原代人脑膜瘤细胞中。这些数据 与升高的SGK1转录表达和升高的SGK1蛋白表达一致 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双MTORC1/mtorc2 由阿斯利康（Astrazeneca）提供的抑制剂AZD2014在原代人脑膜瘤细胞系中提供。我们的数据令人信服 表明人脑膜瘤细胞中MTORC2依赖性SGK1的激活对AZD2014敏感，但 对雷帕霉素不敏感。 AZD2014在体外治疗原发性脑膜瘤细胞，无论是NF2缺陷剂还是 表达NF2的，导致细胞增殖降低，疗效比雷帕霉素更大。此外，与众不同 Rapamycin，AZD2014不会引起Provival途径的激活，例如PI3K/AKT/SGK1。在这个 提案，研究人员与阿斯利康合作，建议测试AZD2014对患者的影响 与II级和III型脑膜瘤的经常性或进步性。这将是一个单臂，多中心开放的 标签，II期研究，以评估AZD2014的疗效，安全性和耐受性 手术切除和辐射后II-III级脑膜瘤。该研究的主要目的是估计 队列的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，以定义脑膜瘤亚组是否对AZD2014的反应更好。这 研究应牢固确定AZD2014是否是未来更大随机的重要候选药物 脑膜瘤试验。