Therapeutic efficacy of the CRL inhibitor MLN4924 in NF2 mutant mesothelioma

CRL抑制剂MLN4924对NF2突变型间皮瘤的治疗效果

• 批准号: 10542988
• 负责人: FILIPPO G GIANCOTTI
• 金额: $ 31.31万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542988
• 关键词: Therapeutic; efficacy; CRL; inhibitor; MLN4924

 DESCRIPTION (provided by applicant): Patients with advanced malignant mesothelioma (MM) have limited treatment options. The standard first-line chemotherapy regimen, pemetrexed/cisplatin, improves survival compared to cisplatin alone from 9 to 12 months. In order to develop mechanism-based therapies for MM, it is important to identify the oncogenic mutations and signaling pathways that drive its development and sustain its maintenance. Although about 75% of MM carry mutations at the NF2 locus, which encodes Merlin. We have discovered that inactivation of Merlin drives the development and maintenance of MM by activating the pro-oncogenic E3 ubiquitin Cullin Ring Ligase CRL4DCAF1, which in turn inhibits the Hippo pathway tumor suppressor kinases Lats1/2. Our Preliminary Studies indicate that the CRL inhibitor MLN4924, developed by Millenium-Takeda, exhibits exhibit selective preclinical efficacy in NF2 mutant MM cells. In addition, in vitro and in vivo studies indicate that MLN4924 significantly enhances the efficacy of pemetrexed and cisplatin in NF2 mutant MM. To establish the pre-clinical and clinical activity of MLN4924, alone and in combination with chemotherapy, in NF2 mutant MM, we will pursue the following independent, but interrelated Specific Aims: 1) To test the preclinical activity of MLN4924, alone and in combination with chemotherapy, in a novel Genetically Engineered Mouse Model (GEMM) of MM. Nf2Flox/Flox; LucR mice will be injected in their pleural cavity with lentiviruses encoding Cre in combination with short hairpin (sh) RNAs targeting the mRNAs encoded by Cdkn2a or both Cdkn2a and Bap1. Tumor-bearing mice will be treated with MLN4924, pemetrexed/cisplatinum, or both and subjected to bioluminescent imaging to monitor tumor growth. Molecular studies on tumor samples will enable us to verify target inhibition and to determine the mechanism of action of MLN4924. 2) To test the preclinical efficacy of MLN4924, alone and in combination with chemotherapy, in patient-derived xenograft (PDX) models of MPM. PDX models of MMs carrying mutations at the NF2 locus, the BAP1 locus, or at both loci will be treated with MLN4924, alone and in combination with cispatin/pemetrexed, and the results will be examined as described above. The sensitivity of prospectively isolated cancer stem cells to the drugs will be examined in tumor organoid cultures. 3) To test the clinical efficacy of MLN4924 by conducting a phase I/II trial in patients with pleural or peritoneal MM. We will conduct a single institution trial comprising two cohorts: 1 a phase II trial of single agent MLN4924 in patients with NF2 mutant MM, and 2) a phase I trial combining MLN4924 with pemetrexed/cisplatin in previously untreated patients. Information gained from pre-clinical studies in the newly developed GEMM model and state-of-the-art PDX models will help to refine the analysis of patient samples from the clinical trial and, conversely, information gained from the clinical trial will motivate additional pre-clinical studies. We envisin that mechanism-based therapies, such as the one proposed here, will radically improve the outcome of patients with MM.

 描述（由申请人提供）：晚期恶性间皮瘤（MM）患者的治疗选择有限。与顺铂单药治疗相比，标准一线化疗方案培美曲塞/顺铂可延长9至12个月的生存期。为了开发基于机制的MM治疗方法，重要的是要确定致癌突变和信号通路，驱动其发展和维持其维持。尽管约75%的MM在编码Merlin的NF 2基因座处携带突变。我们发现Merlin的失活通过激活原癌基因E3泛素Cullin环连接酶CRL 4DCAF 1，进而抑制Hippo途径肿瘤抑制激酶Lats 1/2，从而驱动MM的发展和维持。我们的初步研究表明，由Millenium-Takeda开发的CRL抑制剂MLN 4924在NF 2突变型MM细胞中显示出选择性临床前疗效。此外，体外和体内研究表明，MLN 4924可显著增强培美曲塞和顺铂在NF 2突变型MM中的疗效。为了确定MLN 4924单独给药和与化疗联合给药在NF 2突变型MM中的临床前和临床活性，我们将追求以下独立但相互关联的特定目的：1）在MM. Nf 2 Flox/Flox的新型遗传工程小鼠模型（GEMM）中检测MLN 4924单独给药和与化疗联合给药的临床前活性; LucR小鼠将在其胸膜腔中注射编码Cre的慢病毒与短发夹（sh）靶向由Cdkn 2a或Cdkn 2a和Bap 1编码的mRNA的RNA。荷瘤小鼠将接受MLN 4924、培美曲塞/顺铂或两者治疗，并进行生物发光成像以监测肿瘤生长。对肿瘤样本的分子研究将使我们能够验证MLN 4924的靶向抑制作用并确定其作用机制。2)在MPM患者源性异种移植（PDX）模型中检测MLN 4924单独给药和与化疗联合给药的临床前疗效。在NF 2基因座、BAP 1基因座或两个基因座均携带突变的PDX模型将接受MLN 4924单独给药和与顺铂/培美曲塞联合给药，并按照上述方法检查结果。将在肿瘤类器官培养物中检查前瞻性分离的癌症干细胞对药物的敏感性。3)通过在胸膜或腹膜MM患者中进行I/II期试验来检测MLN 4924的临床疗效。我们将进行一项包括两个队列的单机构试验：1在NF 2突变型MM患者中进行的MLN 4924单药治疗的II期试验，和2）在既往未经治疗的患者中进行的MLN 4924与培美曲塞/顺铂联合治疗的I期试验。从新开发的GEMM模型和最先进的PDX模型中的临床前研究中获得的信息将有助于完善临床试验中患者样本的分析，反之亦然， 从临床试验中获得的信息将促进额外的临床前研究。我们设想，机制为基础的治疗，如这里提出的，将从根本上改善MM患者的结果。

项目成果

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• DOI: 10.1038/s41556-018-0138-8
• 发表时间: 2018-08
• 期刊: Nature cell biology
• 影响因子: 21.3
• 作者: Er EE;Valiente M;Ganesh K;Zou Y;Agrawal S;Hu J;Griscom B;Rosenblum M;Boire A;Brogi E;Giancotti FG;Schachner M;Malladi S;Massagué J
• 通讯作者: Massagué J

Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis.

• DOI: 10.1158/1535-7163.mct-16-0821
• 发表时间: 2017-08
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Cooper J;Xu Q;Zhou L;Pavlovic M;Ojeda V;Moulick K;de Stanchina E;Poirier JT;Zauderer M;Rudin CM;Karajannis MA;Hanemann CO;Giancotti FG
• 通讯作者: Giancotti FG