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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：
10488225
负责人：
MICHAEL E. BERENS
金额：
$ 20.06万
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/10488225
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 Recurrence Research Project Grants Resected Role Safety Sampling Signal Transduction Specificity Stream System TOP2A gene Teniposide Testing TimeLine Toxic effect Ubiquitin Up-Regulation Work Xenograft Model Xenograft procedure 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 predictive test protein degradation response small molecule small molecule inhibitor synergism targeted agent therapeutic target 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/蛋白酶体系统内的一种特定途径，在胶质母细胞瘤中过度活跃（GBM），其上调与神经胶质瘤进展和较差的生存率有关。佩沃内司他是一种一流的小分子 neddylation 抑制剂，可影响蛋白质降解并抑制细胞生长培养物和原位异种移植物中的 GBM 细胞。 Pevonedistat 正在进行临床试验并可通过 NCI 获得癌症治疗评估计划（CTEP）。因为 GBM 内部和之间的分子异质性患者模糊了治疗目标并混淆了临床试验中的疗效信号，我们建议使用模型子集中目标代理的分子“漏洞签名”，并使用这些签名指导早期临床试验的患者入组。我们的初步数据揭示了分子决定因素联合pevonedistat与PTEN缺失（PTENdel）和PTEN突变（PTENmt）GBM的协同作用 TOP2A 抑制剂，依托泊苷。我们假设特定的“协同特征”可用于识别患者可能对 pevonedistat + 依托泊苷产生反应，并提出一项签名指导的临床试验，以实现协同作用复发性 GBM (rGBM) 患者。我们提出以下目标：目标 1. 发现并验证 pevonedistat + TOP2Ais 在 GBM 中协同抗肿瘤的机制。我们将使用GBM 患者来源的异种移植（PDX）外植体培养物和原位肿瘤以实现这一目标，并将验证拟定临床试验中患者肿瘤样本中“协同特征”的预测性能目标 3. 目标 2. 在 GBM 中单独验证 pevonedistat 的“漏洞签名”。我们将使用 GBM PDX 文化和原位模型来完善和测试“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”中的安全性标志性的 rGBM 患者正在进行 I 期临床试验。我们将把具有“协同标志性”GBM 的患者招募到一个 pevonedistat + 依托泊苷的 I 期研究以确定最大耐受剂量/推荐的 II 期研究联合治疗的剂量；获取初步响应数据；定义神经药代动力学 (nPK) 使用脑内微透析的pevonedistat；并评估神经药效学（nPD） pevonedistat 在研究参与者子集中使用机会窗口设计。该项目依赖支持来自用于 nPK 分析的核心 A，用于外显子组和 RNA 测序和生物信息学的核心 B，以及用于分析的管理核心与项目 1 和 2 协调和集成，以实现数据共享和漏洞签名比较 OV-αCD47-G1 和他喹莫德。如果成功，我们的项目将在以下环境中推进药物开发：迄今为止，通过将 GBM 分子亚群与药物发现/开发和招募患者以最大可能将精准医学引入护理流程。