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

基本信息

批准号：
9028689
负责人：
FILIPPO G GIANCOTTI
金额：
$ 52.54万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2016-01-01 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9028689
关键词：
Agar Binding CDKN2A gene Cell Nucleus Cell Proliferation Cell Survival Cells Chemotherapy-Oncologic Procedure Cisplatin Clinic Clinical Clinical Trials Contact Inhibition Cullin Proteins DNA Repair Development Drug effect disorder Enzymes Exhibits Extracellular Matrix Gene Expression Genetically Engineered Mouse Growth Image Immunoblotting In Vitro Institution Ligase Maintenance Malignant Mesothelioma of Peritoneum Malignant Neoplasms Malignant mesothelioma Mediating Mesothelioma Messenger RNA Modeling Molecular Monitor Mus Mutation Neurofibromatosis 2 Neurofibromin 2 Nuclear Oncogenic Organoids Output Pathway interactions Patients Pemetrexed Pharmaceutical Preparations Phase I/II Trial Phosphotransferases Pleural Pleural cavity Preclinical Testing Proliferating Proteins Regimen Repression Safety Sampling Signal Pathway Signal Transduction Site Subfamily lentivirinae TP53 gene Tertiary Protein Structure Testing Therapeutic Transcription Coactivator Transcriptional Activation Treatment Efficacy Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Volume Ubiquitin Ubiquitin Like Proteins Xenograft Model Xenograft procedure base cancer stem cell chemotherapy chromatin remodeling clinical efficacy cohort conformer efficacy testing flexibility improved improved outcome in vivo inhibitor/antagonist mouse model mutant neoplastic cell novel novel therapeutics p19ARF phase I trial phase II trial pre-clinical preclinical efficacy preclinical study public health relevance research clinical testing small hairpin RNA small molecule tumor tumor growth tumorigenesis ubiquitin-protein ligase

项目摘要

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，与单独使用顺铂相比，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。尽管约 75% 的 MM 携带突变，但识别驱动其发展和维持其维持的致癌突变和信号通路非常重要。我们发现，编码 Merlin 的 NF2 基因座的失活通过激活促癌 E3 泛素 Cullin 环连接酶 CRL4DCAF1 来驱动 MM 的发生和维持，而 CRL4DCAF1 又会抑制 Hippo 通路肿瘤抑制激酶 Lats1/2。研究表明，Millenium-Takeda 开发的 CRL 抑制剂 MLN4924 在以下疾病中表现出选择性临床前疗效：此外，体外和体内研究表明，MLN4924 显着增强培美曲塞和顺铂在 NF2 突变 MM 中的疗效，以确定 MLN4924 单独使用以及与化疗联合使用的临床前和临床活性。 NF2突变体MM，我们将追求以下独立但相互关联的具体目标：1）测试临床前活性MLN4924，单独或与化疗联合，在 Nf2Flox/Flox 的新型基因工程小鼠模型 (GEMM) 中；LucR 小鼠的胸膜腔中注射编码 Cre 的慢病毒，并结合靶向将用 Cdkn2a 或 Cdkn2a 和 Bap1 编码的 mRNA 治疗荷瘤小鼠。 MLN4924、培美曲塞/顺铂或两者并进行生物发光成像以监测肿瘤生长，这将使我们能够验证目标抑制并确定 MLN4924 的作用机制 2) 测试 MLN4924 的临床前疗效。在携带突变的 MM 的 PDX 模型中单独使用或与化疗联合使用。 NF2 基因座、BAP1 基因座或两个基因座将单独用 MLN4924 或与顺斯帕汀/培美曲塞联合治疗，并且将如上所述检查结果。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 期试验来测试 MLN4924 的临床疗效。将进行一项由两个队列组成的单一机构试验：1）在 NF2 突变 MM 患者中进行单一药物 MLN4924 的 II 期试验，2）在先前未经治疗的患者中进行 MLN4924 与培美曲塞/顺铂联合的 I 期试验。新开发的 GEMM 模型和最先进的 PDX 模型的研究将有助于完善对临床试验中患者样本的分析，相反，从临床试验中获得的信息将激发更多的临床前研究，我们设想基于机制的疗法（例如本文提出的疗法）将从根本上改善 MM 患者的治疗结果。