MDM2 inhibitor therapy for TP53 wild-type GBM

MDM2 抑制剂治疗 TP53 野生型 GBM

• 批准号: 10492775
• 负责人: Jann N. Sarkaria
• 金额: $ 15.52万
• 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/10492775
• 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; inhibitor therapy; 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p53功能的破坏是癌症中最常见的改变，导致 遗传毒性损伤后DNA修复的失调。使用小分子抑制剂阻止 p53与鼠的相互作用2（MDM2）可防止MDM2介导的p53降解，IS 针对这种关键DNA损伤响应途径的最先进的策略。在这个项目中，我们 引入高潜在的MDM2抑制剂BI-907828作为针对胶质母细胞瘤的新型治疗方法 （GBM）。这种一流的MDM2抑制剂在单位纳摩尔的GBM PDX中具有很高的潜力 浓度。 BI-907828单药治疗具有针对原位GBM PDX的显着抗肿瘤活性 靶向药效药物药物效应的相应强大证据 - p53的稳定和增加 p53介导的促凋亡基因的转录。此外，将治疗与BI-907828和辐射合并 明显增强了外在和内在凋亡途径中的促凋亡基因的诱导，以及 原位PDXS中的辐射/BI-907828治疗导致动物生存的深刻扩展 两个GBM PDX。这种活性在已知具有完整血脑屏障的原位PDX模型中是 由于BI-907828的分布相对有限，因此特别有趣。与 促有丝分裂信号传导或许多其他DNA修复目标的调节，这需要持续的高级 抑制最佳效应，MDM2在负反馈回路中严格调节p53的稳定性。那，我们 假设即使短期抑制MDM2活性也会导致p53表达的增加足够 激活p53的促凋亡作用。定义靶向不同的药理效应的差异 调节电路的类型（例如，正面合作信号网络与负反馈转录 网络）代表了计划项目的关键创新。该项目的具体目的是： AIM 1：开发PK→PD→BI-907828单一疗法的疗效模型 目标2：进行0阶段试验以评估BI-907828在GBM中的分布和药效学 AIM 3：确定BI-907828与新诊断为GBM患者的辐射的耐受性 目标4：评估BI-907828的组合策略与其他抗癌疗法的GBM