Signature-guided treatment of GBM with neddylation inhibitor pevonedistat

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的动态平衡。 去核是泛素/蛋白酶体系统中的一条特殊途径，在胶质母细胞瘤中过度活跃 (GBM)，并且其上调与胶质瘤的进展和更差的生存相关。Pevonedisat 是一种一流的小分子代谢抑制剂，可以影响蛋白质的降解和抑制肿瘤的生长 培养中的GBM细胞和原位异种移植。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内部和跨GBM的分子异质性 在临床试验中，患者模糊治疗目标和混淆疗效信号，我们建议使用 分子对模型子集中的目标代理的“脆弱性签名”，并使用这些签名来 指导患者参加早期临床试验。我们的初步数据揭示了 培哚地塞米松对PTEN缺失(PTENdel)和PTEN突变(PTENmt)GBM的协同作用 TOP2A抑制剂依托泊苷。我们假设一个特定的“协同签名”可以用来识别病人 可能对pevoneDistat依托泊苷有反应，并提出一项签名指导的临床试验，以实现 复发性基底膜(RGBM)患者。我们提出了以下目标：目标1.发现并验证 聚维酮地塞米松对大鼠肾小球系膜细胞的抗肿瘤作用机制。我们将使用GBM 患者来源的异种移植(PDX)外植体培养和原位肿瘤以追求这一目标，并将验证 年拟议的临床试验中患者肿瘤样本中“协同签名”的预测性能 目标3.目标2.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，以改进和测试“易受攻击性签名”的预测准确性 用于未来的临床试验。目的3.在“增效剂”中测定培冯地塞特依托泊苷的安全性 签名“正在进行I期临床试验的rGBM患者。我们将招收具有“协同签名”的GBM患者加入 确定最大耐受量/推荐剂量的第一阶段研究 联合治疗的剂量；获得初步反应数据；定义神经药物动力学(NPK) 脑内微透析治疗，并评价其神经药效学。 在研究参与者的子组中使用机会窗设计进行pevonedisat。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序列及生物信息学，管理核心用于 与项目1和项目2进行协调和整合，以共享数据和比较脆弱性签名 对OV-αCD47-G1和他喹莫特。如果成功，我们的项目将推动药物开发在 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，以获得将精准医疗输送到护理流中的最高可能性。

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.