MDM2 inhibitor therapy for TP53 wild-type GBM

项目摘要-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， 遗传毒性损伤后DNA修复失调。使用小分子抑制剂阻断 p53与鼠双微体2（MDM 2）相互作用阻止MDM 2介导的p53降解， 这是针对这一关键DNA损伤反应途径的最先进的临床策略。本课题 引入高效MDM 2抑制剂BI-907828作为抗胶质母细胞瘤的新型治疗方法 （GBM）。这种同类最佳的MDM 2抑制剂在体外对GBM PDX具有高度效力， 浓度的BI-907828单药治疗对原位GBM PDX具有显著的抗肿瘤活性， 靶向药效学药物作用的相应有力证据-稳定p53和增加 p53介导的促凋亡基因的转录。此外，BI-907828和放疗联合治疗 在外源性和内源性凋亡途径中显著增强促凋亡基因的诱导， 在原位PDX中联合放疗/BI-907828治疗导致动物生存期显著延长， 两个GBM PDX在已知具有完整血脑屏障的原位PDX模型中， 尤其令人感兴趣的是，BI-907828在正常脑中的分布相对有限。相比 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 抑制最佳效应，MDM 2在负反馈回路中紧密调节p53稳定性。因此我们 假设即使是MDM 2活性短期抑制也可导致足够的p53表达增加 激活p53的促凋亡作用。定义靶向不同药物时的药理作用差异 调节电路的类型（例如，正协同信号网络与负反馈转录 网络）是计划项目的一个关键创新。该项目的具体目标是： 目的1：在GBM PDX中开发BI-907828单药治疗的PK→PD→疗效模型 目的2：进行0期试验，以评价BI-907828在GBM中的分布和药效学 目的3：确定BI-907828联合放疗在新诊断GBM患者中的耐受性 目标4：评估BI-907828与其他抗癌疗法治疗GBM的组合策略

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