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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.