MDM2 inhibitor therapy for TP53 wild-type GBM

MDM2 抑制剂治疗 TP53 野生型 GBM

• 批准号: 10704631
• 负责人: Jann N. Sarkaria
• 金额: $ 24.6万
• 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/10704631
• 关键词: Animals; Apoptosis; Apoptotic; Blood - brain barrier anatomy; Brain; Brain Neoplasms; CDKN2A gene; Cell Cycle Arrest; Cellular Stress; Chemotherapy and/or radiation; Clinical; Code; Collaborations; Combined Modality Therapy; 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; Link; MGMT gene; Malignant Neoplasms; Mediating; Modeling; Mus; Mutation; Newly Diagnosed; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; 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; cancer cell; cancer therapy; 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; pharmacologic; 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

项目总结 – 项目 2 肿瘤抑制因子 p53 功能的破坏是癌症中最常见的改变，并导致 基因毒性损伤后 DNA 修复失调。使用小分子抑制剂阻断 p53 与小鼠双微体 2 (MDM2) 的相互作用可防止 MDM2 介导的 p53 降解，并且 针对这一关键 DNA 损伤反应途径的最先进的临床策略。在这个项目中，我们 推出强效 MDM2 抑制剂 BI-907828 作为胶质母细胞瘤的新型治疗方法 （GBM）。这种一流的 MDM2 抑制剂在体外对 GBM PDX 具有单位数纳摩尔浓度的高效力 浓度。 BI-907828 单一疗法对原位 GBM PDX 具有显着的抗肿瘤活性 相应的有力证据证明了靶向药效药物效应——p53 的稳定和增加 p53 介导的促凋亡基因转录。此外，BI-907828 和放射线的联合治疗 显着增强外在和内在凋亡途径中促凋亡基因的诱导，并且 原位 PDX 联合放疗/BI-907828 疗法可显着延长动物存活时间 两个 GBM PDX。已知具有完整血脑屏障的原位 PDX 模型中的这种活性是 特别有趣的是，BI-907828 在正常大脑中的分布相对有限。相比之下 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、高水平的 为了抑制最佳效果，MDM2 在负反馈环路中严格调节 p53 的稳定性。因此，我们 假设即使是短期抑制 MDM2 活性也能导致 p53 表达增加 激活 p53 的促凋亡作用。定义针对不同目标时药理作用的差异 调节回路的类型（例如，正合作信号网络与负反馈转录网络） 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： 目标 1：开发 BI-907828 单药治疗 GBM PDX 的 PK→PD→疗效模型 目标 2：进行 0 期试验以评估 BI-907828 在 GBM 中的分布和药效学 目标 3：确定新诊断 GBM 患者对 BI-907828 联合放疗的耐受性 目标 4：评估 BI-907828 与其他 GBM 抗癌疗法的组合策略