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
基本信息
- 批准号:9753747
- 负责人:
- 金额:$ 38.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-10 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AKT1 geneAdjuvantAdultAdvanced Malignant NeoplasmAgreementAllelesArachnoid materBehaviorBiological AssayBrain NeoplasmsCCI-779Cell LineCell ProliferationCell SurvivalCellsClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsComplexCytostaticsDataDisclosureEnrollmentExcisionFRAP1 geneFutureGAB1 geneGene SilencingGenesGenetic TranscriptionGenetic studyGrantHumanImmunohistochemistryIn VitroIntracranial NeoplasmsMalignant NeoplasmsModelingMolecularMolecular AnalysisMorbidity - disease rateMutationNeurilemmomaNeurofibromatosis 2Neurofibromin 2Null LymphocytesOperative Surgical ProceduresOther GeneticsOutcomePathway interactionsPatientsPharmaceutical PreparationsPhasePhosphotransferasesProgression-Free SurvivalsPublic HealthRadiationRandomizedRecurrenceReportingResearch PersonnelResectedSDZ RADSafetySalvage TherapySgk proteinSignal PathwaySignal TransductionSirolimusSubgroupTechniquesTestingToxic effectTumor TissueUnited StatesUnited States National Institutes of HealthWorkarmcell growthchemotherapycohortdrug candidateefficacy testingexperiencegenetic analysisgenome editinginhibitor/antagonistmeningiomanovelopen labelphase 2 studyphase II trialpre-clinicalprimary endpointprotein expressionrandomized trialrapid growthresponsesecondary endpointsmall hairpin RNAsmoothened signaling pathwaystandard of caretumortumor registry
项目摘要
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.
脑膜瘤是由脑膜上皮蛛网膜帽细胞产生的肿瘤,是最常见的肿瘤
成人原发性颅内肿瘤。 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,生长速度快,复发率增加。目前的
脑膜瘤的护理标准是最大程度安全的手术切除,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 WHO II 级或 III 级)。进展的脑膜瘤
尽管手术和放射导致高发病率。目前尚无已证实对患者有效的化疗方法
因此,对于侵袭性脑膜瘤,非常需要有效的非侵入性治疗。最常见的
散发性脑膜瘤的遗传改变是 50-60% 的肿瘤中双等位基因 NF2 基因失活。我们早期的
研究确定 NF2 蛋白 merlin 是 mTORC1 信号传导的新型负调节因子,这导致
使用变构 mTORC1 抑制剂雷帕霉素类似物 RAD001/依维莫司治疗 NF2 和
脑膜瘤患者。迄今为止的临床结果似乎显示出细胞抑制作用,这与
我们的雷帕霉素体外结果。 mTOR 是一种进化上保守的 Ser/Thr 激酶,可调节细胞
通过两种不同的功能复合物 mTORC1 和 mTORC2 来实现生长、增殖和存活。在我们的
最近的研究中,我们检测到 mTORC2 依赖性 AGC 激酶 SGK1(血清和
糖皮质激素调节激酶 1) 在有或没有 NF2 丢失的原代人脑膜瘤细胞中。这些数据
与 SGK1 转录表达升高和 SGK1 蛋白表达升高一致
我们在人类脑膜瘤中观察到。这些观察结果促使我们测试选择性双 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 mTORC2 依赖性 SGK1 的激活对 AZD2014 敏感,但
对雷帕霉素不敏感。 AZD2014 对原发性脑膜瘤细胞的体外治疗,无论是 NF2 缺陷型还是
表达 NF2 会导致细胞增殖减少,且比雷帕霉素更有效。此外,与
雷帕霉素、AZD2014 不会引起 PI3K/Akt/SGK1 等促生存途径的激活。在这个
根据提案,研究人员与阿斯利康合作,提议测试 AZD2014 对患者的效果
复发性或进展性 WHO II 级和 III 级脑膜瘤。这将是一个单臂、多中心、开放式
标签、II 期研究评估 AZD2014 在 30 名复发性乳腺癌患者中的疗效、安全性和耐受性
手术切除和放射治疗后的 II-III 级脑膜瘤。该研究的主要目的是估计
该队列的 6 个月无进展生存期。进一步,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 反应更好。这
研究应确定 AZD2014 是否是未来更大规模随机对照试验的重要候选药物
脑膜瘤试验。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Scott R Plotkin其他文献
Evolving concepts in meningioma management in the era of genomics.
基因组学时代脑膜瘤管理概念的演变。
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:6.2
- 作者:
Annie L Hsieh;W. L. Bi;V. Ramesh;Priscilla K Brastianos;Scott R Plotkin - 通讯作者:
Scott R Plotkin
Integrating Ataxia Evaluation into Tumor-Induced Hearing Loss Model to Comprehensively Study NF2-Related Schwannomatosis
将共济失调评估融入肿瘤性听力损失模型,全面研究 NF2 相关神经鞘瘤病
- DOI:
10.3390/cancers16111961 - 发表时间:
2024-05-22 - 期刊:
- 影响因子:5.2
- 作者:
Simeng Lu;Zhenzhen Yin;Jie Chen;Limeng Wu;Yao Sun;Xing Gao;Peigen Huang;Justin Jordan;Scott R Plotkin;Lei Xu - 通讯作者:
Lei Xu
Effect of NFX-179 MEK inhibitor on cutaneous neurofibromas in persons with neurofibromatosis type 1
NFX-179 MEK 抑制剂对 1 型神经纤维瘤病患者皮肤神经纤维瘤的影响
- DOI:
10.1126/sciadv.adk4946 - 发表时间:
2024-05-01 - 期刊:
- 影响因子:13.6
- 作者:
K. Sarin;Mark Bradshaw;Chris O'Mara;J. Shahryari;John Kincaid;Steven Kempers;John H Tu;Sunil Dhawan;Janet DuBois;David Wilson;Patrice Horwath;Mark P de Souza;Christopher Powala;Gerd G Kochendoerfer;Scott R Plotkin;Guy F Webster;Lu Q Le - 通讯作者:
Lu Q Le
Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models
针对 NF2 神经鞘瘤模型中的 cMET 通路可增强放射反应,且不会对听力产生不利影响
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Yingchao Zhao;Pinan Liu;Na Zhang;Jie Chen;Lukas D. L;egger;Limeng Wu;Fu Zhao;Yanling Zhang;Jing Zhang;Takeshi Fujita;Anat Stemmer-Rachamimov;Gino B. Ferraro;Hao Liu;Alona Muzikansky;Scott R Plotkin;Konstantina M. Stankovic;Rakesh K. Jain;Lei Xu - 通讯作者:
Lei Xu
Scott R Plotkin的其他文献
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{{ truncateString('Scott R Plotkin', 18)}}的其他基金
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 - 财政年份:2016
- 资助金额:
$ 38.9万 - 项目类别:
Developing Endpoints to Facilitate Clinical Trials in Rare Diseases
开发终点以促进罕见疾病的临床试验
- 批准号:
9052881 - 财政年份:2015
- 资助金额:
$ 38.9万 - 项目类别:
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