权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Signature-guided treatment of GBM with neddylation inhibitor pevonedistat

使用 neddylation 抑制剂 pevonedistat 进行特征引导治疗 GBM

基本信息

批准号：
10696195
负责人：
MICHAEL E. BERENS
金额：
$ 19.62万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-13 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696195
关键词：
Bioinformatics Biological Products Biometry Bortezomib Cancer Therapy Evaluation Program Caring Cells Clinical Trials Combined Modality Therapy Correlative Study Coupled DNA Data Development Dose Drug Targeting Eligibility Determination Enrollment Etoposide Future Genes Glioblastoma Glioma Goals Growth Heterogeneity Homeostasis Link Malignant Glioma Malignant Neoplasms Maximum Tolerated Dose Microdialysis Modeling Molecular Molecular Profiling Mutate Outcome PTEN gene Participant Pathway interactions Patient Recruitments Patient-Focused Outcomes Patients Penetration Performance Pharmaceutical Preparations Phase Phase I Clinical Trials Phenotype Play Pre-Clinical Model Proteasome Inhibitor Proteins Recommendation Recurrence Research Project Grants Resected Role Safety Sampling Signal Transduction Specificity Stream System TOP2A gene Teniposide Testing Toxic effect Ubiquitin Up-Regulation Work Xenograft Model Xenograft procedure candidate identification data sharing design drug development drug discovery exome exome sequencing genomic signature improved in vitro Model in vivo inhibitor molecular subtypes multicatalytic endopeptidase complex participant enrollment patient derived xenograft model phase 1 study precision medicine predicting response protein degradation response small molecule small molecule inhibitor synergism targeted agent therapeutic target timeline transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY – PROJECT 3 The ubiquitin/proteasome system maintains intracellular homeostasis via degradation of unwanted proteins. Neddylation is a specific pathway within the ubiquitin/proteasome system that is overactive in glioblastoma (GBM), and whose upregulation has been associated with glioma progression and worse survival. Pevonedistat is a first-in-class small-molecule neddylation inhibitor shown to impact protein degradation and inhibit growth of GBM cells in culture and orthotopic xenografts. Pevonedistat is in clinical trials and available through NCI’s Cancer Therapy Evaluation Program (CTEP). Because the molecular heterogeneity within and across GBM patients obscures therapeutic targets and obfuscates signals of efficacy in clinical trials, we propose the use of molecular “signatures of vulnerability” to targeted agents in subsets of models, and to use these signatures to guide patient enrollment in early-stage clinical trials. Our preliminary data revealed molecular determinants of synergy against PTEN-deleted (PTENdel) and PTEN-mutated (PTENmt) GBM from combining pevonedistat with a TOP2A inhibitor, etoposide. We hypothesize that a specific “synergy signature” can be used to identify patients likely to respond to pevonedistat + etoposide and propose a signature-guided clinical trial to achieve synergy in patients with recurrent GBM (rGBM). We propose the following Aims: Aim 1. Discover and validate the mechanism underlying the antitumor synergy of pevonedistat + TOP2Ais in GBM. We will use GBM patient-derived xenograft (PDX) explant cultures and orthotopic tumors to pursue this aim and will validate the predictive performance of the “synergy signature” in patient tumor samples from the proposed clinical trial in Aim 3. Aim 2. Validate a “signature of vulnerability” to pevonedistat alone in GBM. We will use GBM PDX cultures and orthotopic models to refine and test the predictive accuracy of a “signature of vulnerability” to pevonedistat for future clinical trials. Aim 3. Determine the safety of pevonedistat + etoposide in “synergy signature” rGBM patients in a phase I clinical trial. We will enroll patients with “synergy signature” GBM to a phase I study of pevonedistat + etoposide to determine the maximum tolerated dose/recommended phase II dose of the combination therapy; obtain preliminary response data; define the neuropharmacokinetic (nPK) of pevonedistat using intracerebral microdialysis; and evaluate the neuropharmacodynamics (nPD) of pevonedistat using a window of opportunity design in subsets of study participants. This project relies on support from Core A for nPK analysis, Core B for exome and RNA Seq and bioinformatics, and the Admin Core for coordination and integration with Projects 1 and 2 for data sharing and comparison of signatures of vulnerability to OV-αCD47-G1 and tasquinimod. If successful, our project will advance drug development in the setting of a heretofore recalcitrant tumor by linking molecular subsets of GBM with both drug discovery/development and patient recruitment for highest likelihood of conveying precision medicine into the care stream.

项目概要-项目3 泛素/蛋白酶体系统通过降解不需要的蛋白质来维持细胞内稳态。 Neddylation是泛素/蛋白酶体系统中的一个特异性通路，在胶质母细胞瘤中过度活跃 (GBM)并且其上调与胶质瘤进展和更差的存活率相关。Pevonedistat 是一种一流的小分子neddylation抑制剂，可影响蛋白质降解并抑制 GBM细胞培养和原位异种移植。Pevonedistat正在进行临床试验，可通过NCI的癌症治疗评估计划（CTEP）。因为GBM内部和之间的分子异质性患者模糊了治疗靶点，模糊了临床试验中的疗效信号，我们建议使用在模型的子集中，针对目标代理的分子“脆弱性签名”，并使用这些签名来指导早期临床试验的患者入组。我们的初步数据显示， pevonedistat与pevonedistat联合治疗对PTEN缺失（PTENdel）和PTEN突变（PTENmt）GBM的协同作用 TOP 2A抑制剂依托泊苷。我们假设一个特定的“协同签名”可以用来识别患者可能对pevonedistat +依托泊苷有反应，并建议进行一项特征指导的临床试验，以在复发性GBM（rGBM）患者。我们提出以下目标：目标1。发现并验证 pevonedistat + TOP 2Ais在GBM中的抗肿瘤协同作用的潜在机制。我们将使用GBM 患者来源的异种移植物（PDX）外植体培养物和原位肿瘤来实现这一目标，并将验证在来自2010年的拟议临床试验的患者肿瘤样品中“协同作用特征”的预测性能目标3.目标二。在GBM中单独使用pevonedistat可获得“脆弱性特征”。我们将使用GBM PDX 文化和原位模型，以完善和测试“脆弱性特征”的预测准确性， pevonedistat用于未来的临床试验。目标3.确定pevonedistat +依托泊苷在“协同作用”中的安全性在I期临床试验中的rGBM患者。我们将招募具有“协同特征”GBM的患者， Pevonedistat +依托泊苷的I期研究，以确定最大耐受剂量/推荐的II期联合治疗的剂量;获得初步反应数据;定义联合治疗的神经药代动力学（nPK）使用脑内微透析进行pevonedistat;并评价神经药效学（nPD） pevonedistat在研究受试者亚组中使用机会窗设计。这个项目依赖于支持核心A用于nPK分析，核心B用于外显子组和RNA Seq和生物信息学，以及管理核心用于与项目1和项目2协调和整合，以共享数据和比较脆弱性特征 OV-α CD 47-G1和他喹莫德。如果成功的话，我们的项目将在全球范围内推动药物开发。迄今为止，通过将GBM的分子亚群与药物发现/开发和招募患者，以最大可能地将精准医疗输送到护理流程中。