MDM2 inhibitor therapy for TP53 wild-type GBM

MDM2 抑制剂治疗 TP53 野生型 GBM

• 批准号: 10305366
• 负责人: Jann N. Sarkaria
• 金额: $ 17.28万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10305366
• 关键词: Animals; Apoptosis; Apoptotic; Blood - brain barrier anatomy; Brain; Brain Neoplasms; CDKN2A gene; Cell Cycle Arrest; Cellular Stress; Clinical; Code; Collaborations; DNA Damage; DNA Repair; Data; Digit structure; Dose; Double Minutes; Drug Kinetics; Drug Targeting; Feedback; Genes; Genetic Transcription; Genomic Instability; Genotoxic Stress; Glioblastoma; Half-Life; Heel; In Vitro; Isocitrate Dehydrogenase; Lead; Link; MGMT gene; Malignant Neoplasms; Mediating; Modeling; Mus; Mutation; Newly Diagnosed; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase 0 Trial; Phase I Clinical Trials; Plasma; Radiation; Radiation therapy; Regimen; Regulation; Resistance; Sampling Studies; Series; Signal Pathway; Signal Transduction; Structure; TP53 gene; Testing; Therapeutic; Tissues; Transcriptional Regulation; Treatment Efficacy; Tumor Suppressor Proteins; Ubiquitination; base; cancer cell; cancer therapy; chemotherapy; clinical development; combinatorial; conventional therapy; drug distribution; first-in-human; fractionated radiation; genome integrity; genotoxicity; improved outcome; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; nanomolar; novel therapeutic intervention; patient derived xenograft model; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; pre-clinical; prevent; response; restoration; senescence; small molecule; small molecule inhibitor; success; temozolomide; therapeutic target; tumor; tumorigenesis

Project Summary – Project 2 Disruption of tumor suppressor p53 function is the most common alteration in cancer and results in dysregulation of DNA repair following genotoxic insults. Use of small molecule inhibitors blocking the interaction of p53 with murine double minute 2 (MDM2) prevents MDM2-mediated degradation of p53 and is the most clinically advanced strategy to target this critical DNA damage response pathway. In this project, we introduce the highly potent MDM2 inhibitor BI-907828 as a novel therapeutic approach against glioblastoma (GBM). This best-in-class MDM2 inhibitor is highly potent in vitro in GBM PDXs at single-digit nanomolar concentrations. BI-907828 monotherapy has significant anti-tumor activity against orthotopic GBM PDXs with corresponding robust evidence of on-target pharmacodynamic drug effects – stabilization of p53 and increased p53-mediated transcription of pro-apoptotic genes. Further, combined therapy with BI-907828 and radiation markedly enhances induction of pro-apoptotic genes in both the extrinsic and intrinsic apoptotic pathway, and combined radiation/BI-907828 therapy in orthotopic PDXs results in profound extension of animal survival in two GBM PDXs. This activity in orthotopic PDX models known to have an intact blood brain barrier is especially interesting since BI-907828 has relatively limited distribution into normal brain. In contrast to modulation of mitogenic signaling or many other DNA repair targets, which require sustained, high-level suppression of optimal effects, MDM2 tightly regulates p53 stability in a negative feedback loop. Thus, we hypothesize that even short-term inhibition of MDM2 activity can lead to increased expression of p53 sufficient to activate pro-apoptotic effects of p53. Defining the differences in pharmacologic effect when targeting distinct types of regulatory circuits (e.g., positively cooperative signaling networks vs. negative feedback transcriptional networks) represents a key innovation of the planned project. The specific Aims of the project are: Aim 1: Develop a PK→PD→efficacy model for BI-907828 monotherapy in GBM PDXs Aim 2: Conduct a phase 0 trial to evaluate the distribution and pharmacodynamics of BI-907828 in GBM Aim 3: Determine the tolerability of BI-907828 combined with radiation in patients with newly diagnosed GBM Aim 4: Evaluate combinatorial strategies for BI-907828 with other anticancer therapies for GBM

项目摘要-项目2 肿瘤抑制基因P53功能的中断是癌症中最常见的改变，并导致 遗传毒性侮辱后DNA修复的失调。使用小分子抑制剂阻断 P53与小鼠双分钟2(MDM2)的相互作用阻止MDM2介导的P53和IS的降解 针对这一关键的DNA损伤反应途径的最先进的临床策略。在这个项目中，我们 介绍高效mdm2抑制剂BI-907828作为治疗胶质母细胞瘤的新方法 (GBM)。这种最好的MDM2抑制剂在体外对个位数纳米分子的GBM PDX具有很高的效力 浓度。BI-907828单一疗法对原位GBM PDX具有显著的抗肿瘤活性 靶向药效药物效应的相应有力证据--P53的稳定和增强 P53介导的促凋亡基因转录。此外，BI-907828和放射联合治疗 显著增强外源性和内源性凋亡途径中促凋亡基因的诱导，以及 放射/BI-907828联合治疗原位PDX可显著延长动物存活时间 两个GBM PDX。在已知具有完整血脑屏障的原位PDX模型中，这种活动是 特别有趣的是，BI-907828在正常大脑中的分布相对有限。与之形成鲜明对比的是 调节有丝分裂信号或许多其他DNA修复靶点，这需要持续的、高水平的 为了抑制最佳效果，MDM2在负反馈环中严格调节P53的稳定性。因此，我们 假设即使是MDM2活性的短期抑制也可以导致p53表达的增加 激活P53的促凋亡作用。明确靶向不同时的药理作用差异 调节电路的类型(例如，正向协作信号网络与负反馈转录 网络)代表了计划项目的一项关键创新。该项目的具体目标是： 目的1：建立BI-907828单药治疗GBMPDX的PK→PD→疗效模型 目的2：进行0期试验，评价BI-907828在基底膜中的分布和药效学 目的3：确定BI-907828联合放射治疗初诊基底膜患者的耐受性 目的4：评价BI-907828与其他抗癌药物联合治疗基底膜的策略