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.

项目摘要 - 项目3 泛素/蛋白酶体系统通过不良蛋白质降解来维持细胞内稳态。 Neddylation是泛素/蛋白酶体系统内的特定途径，在胶质母细胞瘤中过度活跃（GBM），其上调与神经胶质瘤的进展和生存率较差有关。 pevonedistat 是一种一类小分子的小分子neddylation抑制剂，可影响蛋白质降解并抑制生长培养和原位异种移植物中的GBM细胞。 Pevonedistat正在临床试验中，并通过NCI提供癌症治疗评估计划（CTEP）。因为GBM内部和跨GBM的分子异质性患者掩盖了热目标并混淆临床试验中效率的信号，我们建议使用模型子集中有针对性药物的分子“脆弱性签名”，并将这些签名用于指导患者参加早期临床试验。我们的初步数据揭示了分子决定剂通过将Pevonedistat与PTEN-Muted-Muted-Mutated（PtenMT）GBM进行协同作用 TOP2A抑制剂，依托泊苷。我们假设可以使用特定的“协同签名”来识别患者可能对Pevonedistat +依托泊苷做出反应，并提出一项签名引导的临床试验，以实现协同作用复发性GBM（RGBM）的患者。我们提出以下目的：目标1。发现并验证 GBM中pevonedistat + top2ais的抗肿瘤协同作用的机制。我们将使用GBM 患者衍生的特征（PDX）外植体培养物和原位肿瘤以追求这一目标，并将验证从拟议的临床试验中的患者肿瘤样本中“协同签名”的预测性能目标3。目标2。仅在GBM中验证单独使用Pevonedistat的“脆弱性签名”。我们将使用GBM PDX 培养和原位模型，以完善和测试“脆弱性”的预测准确性 Pevonedistat用于将来的临床试验。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，签名” RGBM患者。我们将注册具有“协同签名” GBM的患者 pevonedistat +依托泊苷的I期研究以确定最大耐受剂量/推荐期II 组合疗法的剂量；获得初步响应数据；定义神经药代动力学（NPK）使用脑内微透析的pevonedistat；并评估神经药物动力学（NPD）在研究参与者的子集中使用机会设计窗口pevonedistat。该项目依靠支持从用于NPK分析的核心A，用于外显子和RNA SEQ和生物信息学的核心B，以及用于与项目1和2的协调和集成，以进行数据共享和比较脆弱性签名到OV-αCD47-G1和Tasquinimod。如果成功，我们的项目将在设置通过将GBM的分子子集与药物发现/发育和发育和发育和患者招募将精确药物传达到护理流的可能性最高的可能性。