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: 10673106
• 负责人: Birgit Knoechel
• 金额: $ 38.22万
• 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/10673106
• 关键词: Affect; Antigens; Apoptosis; Apoptotic; B-Lymphocytes; BCL-2 Protein; BCL2 gene; BCL2L1 gene; 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; Proliferating; 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; biomarker driven; biomarker identification; 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; success; 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.

项目总结 我们的实验室和其他人利用体外和体内的方法来确定潜在的脆弱性 外周T细胞淋巴瘤(PTCL)，可通过小分子或其他方法进行靶向治疗。在这里我们 将重点放在通过知情组合诱导细胞凋亡。在初步数据中，我们表明ALRN- 6924，一种通过抑制与MDM2和MDMX的相互作用来激活野生型p53的装订多肽，是 在PTCL细胞系、体内模型和患者中广泛活跃。第二，我们展示了小分子模拟 在抗细胞凋亡的BH3蛋白中，BCL2、BCL-XL和MCL1可以选择性地用于体外靶向PTCL 并在体内基于对BH3蛋白依赖性的功能评估，称为BH3图谱。这项技术 量化由特定促凋亡多肽诱导的“凋亡启动”的程度，这提供了一种功能 读出细胞对BCL2等个别抗凋亡BH3蛋白的成瘾情况。第三，我们已经建立了和 广泛描述了一组PTCL的体外和体内模型。其中包括&gt；30名患者派生的 10种不同PTCL亚型的异种移植(PDX)和具有间隔特异性的转基因小鼠 PTCL相关转基因的表达。第四，我们使用了PDX模型来执行类似于第二阶段的Pre 抑制MDM2的临床试验，以产生预测性生物标志物，并确定获得性疾病的机制 体内药物治疗期间复发的PDXs的体内耐药性。最后，我们证明了嵌合体 针对Tetraspanin CD37(CART37)的抗原受体T细胞在体外可杀伤PTCL细胞 在活体内。值得注意的是，CART37细胞不会导致自相残杀、杀死人类髓系细胞或靶向非恶性T细胞。 我们的中心目标是开发知情的策略，以改善PTCL患者的预后。确实有 在项目1和2中概述的有希望的新方法，阻止基本信号或针对表观遗传缺陷。 我们将与这些项目密切合作，以确定在具有良好特征的 模型系统和主要样本(来自核心B)。体内获得抵抗力的模型将被审问 识别生物标志物(与Core C一起开发)，用于预测敏感性和治疗方法 抵抗运动。目的1是确定嵌合抗原受体T细胞联合针对 CD37与诱导PTCL细胞凋亡的药物(与Markus Müschen/John Chan，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和桑迪普·戴夫，项目2)。这个项目的数据将被用来选择最有希望的 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(CORE B)，我们将迅速将这些组合转化为生物标记物驱动的针对PTCL患者的人体研究。