Synergistic combinations that target apoptosis induction in PTCL

针对 PTCL 细胞凋亡诱导的协同组合

• 批准号: 9791869
• 负责人: David Marc Weinstock
• 金额: $ 48.15万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791869
• 关键词: Affect; Antigens; Apoptosis; Apoptotic; B-Lymphocytes; BCL-2 Protein; BCL1 Oncogene; BCL2 gene; Biological Markers; Biological Models; CD3 Antigens; CD7 gene; Cell Line; Cells; Clinical Trials; Clinical Trials Network; Collaborations; Data; Defect; Dependence; Development; Epigenetic Process; Goals; Helper-Inducer T-Lymphocyte; Human; IL2RA gene; In Vitro; Individual; Induction of Apoptosis; Intestines; Laboratories; Leukocytes; Liver; Lymphoma; MCL1 gene; MDM2 gene; Malignant - descriptor; Modeling; Mutation; Myeloid Cells; Non-Malignant; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Phosphotransferases; Program Research Project Grants; Proteins; Receptor Signaling; Recurrence; Relapse; Resistance; Sampling; Signal Pathway; Signal Transduction; Spleen; Surface; T Cell Receptor Signaling Pathway; T cell response; T-Cell Lymphoma; T-Cell Receptor; T-Lymphocyte; TP53 gene; Techniques; Therapeutic; Therapeutic Index; Transgenes; Transgenic Mice; Translating; Xenograft Model; Xenograft procedure; addiction; base; biomarker-driven; chimeric antigen receptor T cells; differential expression; improved outcome; in vivo; in vivo Model; inhibitor/antagonist; mimetics; novel strategies; preclinical trial; predictive marker; response; small molecule; synergism; targeted agent; γδ T cells

PROJECT SUMMARY Our laboratory and others have utilized in vitro and in vivo approaches to define potential vulnerabilities in peripheral T-cell lymphomas (PTCLs) that can be targeted with small molecules or other approaches. Here we will focus on the induction of apoptosis through informed combinations. In preliminary data, we show that ALRN- 6924, a stapled peptide that activates wild-type p53 by inhibiting interactions with both MDM2 and MDMX, is broadly active in PTCL cell lines, in vivo models and patients. Second, we show that small molecule mimetics of the anti-apoptotic BH3 proteins BCL2, BCL-xL and MCL1 can be selectively utilized to target PTCLs in vitro and in vivo based on a functional assessment of BH3 protein dependence called BH3 profiling. This technique quantifies the extent of “apoptotic priming” induced by specific proapoptotic peptides, which provides a functional readout of the cell's addiction to individual antiapoptotic BH3 proteins like BCL2. Third, we have established and extensively characterized a panel of in vitro and in vivo models of PTCL. Among these are >30 patient-derived xenografts (PDXs) across 10 different PTCL subtypes and transgenic mice with compartment-specific expression of PTCL-associated transgenes. Fourth, we have used PDX models to perform phase II-like pre- clinical trials of MDM2 inhibition, to generate predictive biomarkers, and to define mechanisms of acquired in vivo resistance with PDXs that relapse during in vivo drug treatment. Finally, we demonstrate that chimeric antigen receptor T cells directed against the tetraspanin CD37 (CART37) can eradicate PTCL cells in vitro and in vivo. Strikingly, CART37 cells do not cause fratricide, kill human myeloid cells or target non-malignant T cells. Our central goal is to develop informed strategies that improve outcomes for patients with PTCL. There are promising new approaches outlined in Projects 1 and 2 that block essential signaling or target epigenetic defects. We will collaborate closely with these Projects to define synergies and antagonisms within well-characterized model systems and primary samples (from Core B). Models with acquired in vivo resistance will be interrogated to identify biomarkers (developed with Core C) that predict sensitivity and therapeutic approaches that overcome the resistance. Aim 1 is to define the effects from combining chimeric antigen receptor T cells directed against CD37 with agents that induce apoptosis in PTCL (with Markus Müschen/John Chan, Project 1). Aim 2 is to define combinations that target PTCL-specific alterations and apoptosis (with Markus Müschen/John Chan, Project 1 and Sandeep Dave, Project 2). The data from this Project will be used to select the most promising combinations that induce PTCL cell apoptosis and eradication. Through our existing clinical trials network (Core B), we will rapidly translate these combinations into biomarker-driven, human studies for patients with PTCL.

项目摘要 我们的实验室和其他实验室已经利用体外和体内方法来确定 外周T细胞淋巴瘤（PTCL），可以用小分子或其他方法靶向。这里我们 将集中在通过知情的组合诱导细胞凋亡。在初步数据中，我们表明ALRN- 6924是一种通过抑制与MDM 2和MDMX的相互作用来激活野生型p53的钉合肽， 在PTCL细胞系、体内模型和患者中具有广泛活性。其次，我们表明，小分子模拟物， 抗凋亡BH 3蛋白BCL 2、BCL-xL和MCL 1可选择性地用于体外靶向PTCL 以及体内基于对BH 3蛋白依赖性的功能评估（称为BH 3谱）。这种技术 量化了由特异性促凋亡肽诱导的“凋亡引发”的程度，这提供了功能性的 读出细胞对单个抗凋亡BH 3蛋白如BCL 2的依赖性。第三，我们已经建立和 广泛表征了一组PTCL的体外和体内模型。其中有>30例患者来源 跨10种不同PTCL亚型的异种移植物（PDX）和具有隔室特异性的转基因小鼠 PTCL相关转基因的表达。第四，我们已经使用PDX模型来执行类似于第二阶段的预处理， MDM 2抑制的临床试验，以产生预测性生物标志物，并确定获得性免疫缺陷的机制。 体内药物治疗期间复发的PDX的体内抗性。最后，我们证明，嵌合 针对四跨膜蛋白CD 37（CART 37）的抗原受体T细胞可以在体外根除PTCL细胞， in vivo.值得注意的是，CART 37细胞不会导致自相残杀，杀死人类骨髓细胞或靶向非恶性T细胞。 我们的中心目标是制定明智的策略，改善PTCL患者的结局。有 在项目1和2中概述的有希望的新方法，阻断必要的信号传导或靶向表观遗传缺陷。 我们将与这些项目密切合作，以确定协同作用和对抗，在良好的特点， 模型系统和主要样品（来自岩心B）。将询问具有获得性体内抗性的模型 确定生物标志物（与核心C开发），预测敏感性和治疗方法，克服 抵抗组织目的1是确定联合嵌合抗原受体T细胞针对 CD 37与诱导PTCL细胞凋亡的药物（与Markus Müschen/John Chan，项目1）。目标二是 定义靶向PTCL特异性改变和细胞凋亡的组合（与MarkusMüschen/JohnChan， 项目1和Sandeep Dave，项目2）。该项目的数据将用于选择最有前途的 诱导PTCL细胞凋亡和根除的组合。通过我们现有的临床试验网络（核心 B），我们将迅速将这些组合转化为生物标志物驱动的PTCL患者的人体研究。