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: 10477038
• 负责人: Birgit Knoechel
• 金额: $ 45.28万
• 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/10477038
• 关键词: Affect; Antigens; Apoptosis; Apoptotic; B-Lymphocytes; BCL-2 Protein; BCL2 gene; BCL2L1 gene; Biological Markers; Biological Models; CD3 Antigens; CD7 gene; Cell Line; Cell Therapy; 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; Lymphoma cell; 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; addiction; antagonist; base; biomarker-driven; chimeric antigen receptor T cells; differential expression; improved outcome; in vivo; in vivo Model; inhibitor; mimetics; novel strategies; patient derived xenograft model; preclinical trial; predictive marker; response; small molecule; stapled peptide; 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.

项目概要 我们的实验室和其他实验室利用体外和体内方法来确定潜在的脆弱性 可以用小分子或其他方法靶向的外周 T 细胞淋巴瘤 (PTCL)。在这里我们 将重点关注通过知情组合诱导细胞凋亡。在初步数据中，我们表明 ALRN- 6924 是一种钉合肽，可通过抑制与 MDM2 和 MDMX 的相互作用来激活野生型 p53 在 PTCL 细胞系、体内模型和患者中广泛活跃。其次，我们证明小分子模拟物 抗凋亡 BH3 蛋白 BCL2、BCL-xL 和 MCL1 可选择性地用于体外靶向 PTCL 体内基于 BH3 蛋白依赖性的功能评估（称为 BH3 分析）。这种技术 量化特定促凋亡肽诱导的“凋亡引发”的程度，这提供了功能性 读出细胞对单个抗凋亡 BH3 蛋白（如 BCL2）的成瘾性。第三，我们建立并 广泛表征了一组 PTCL 的体外和体内模型。其中超过 30 种源自患者 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，我们使用 PDX 模型进行类似 II 期的预- MDM2 抑制的临床试验，产生预测生物标志物，并定义获得性的机制 PDX 的体内耐药性在体内药物治疗期间会复发。最后，我们证明了嵌合体 针对四跨膜蛋白 CD37 (CART37) 的抗原受体 T 细胞可以在体外根除 PTCL 细胞， 体内。引人注目的是，CART37 细胞不会造成自相残杀、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来改善 PTCL 患者的治疗结果。有 项目 1 和项目 2 中概述的有前途的新方法可以阻断必要的信号传导或针对表观遗传缺陷。 我们将与这些项目密切合作，在特征明确的范围内定义协同作用和对抗作用 模型系统和主要样本（来自核心 B）。具有获得性体内耐药性的模型将受到质疑 识别可预测敏感性的生物标志物（使用 Core C 开发）和克服的治疗方法 阻力。目标 1 是确定结合嵌合抗原受体 T 细胞针对 CD37 与诱导 PTCL 细胞凋亡的药物（与 Markus Müschen/John Chan 合作，项目 1）。目标 2 是 定义针对 PTCL 特异性改变和细胞凋亡的组合（与 Markus Müschen/John Chan， 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针对 PTCL 患者的生物标志物驱动的人体研究。