Synergistic combinations that target apoptosis induction in PTCL

针对 PTCL 细胞凋亡诱导的协同组合

基本信息

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
项目类别：
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

项目摘要

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在体外和体内方法中使用了潜在的脆弱性周围T细胞淋巴瘤（PTCLS）可以用小分子或其他方法靶向。我们在这里通过知情组合将重点放在诱导凋亡的诱导上。在初步数据中，我们表明Alrn- 6924是一种通过抑制MDM2和MDMX相互作用来激活野生型p53的阶段肽在PTCL细胞系，体内模型和患者中广泛活跃。其次，我们表明小分子模拟物可以选择性地利用抗凋亡BH3蛋白BCl2，Bcl-XL和MCL1在体外靶向PTCLS 并基于对BH3蛋白依赖的功能评估，称为BH3分析。这项技术量化特定促凋亡肽引起的“凋亡启动”的程度，该肽提供了功能读出细胞对单个抗凋亡BH3蛋白（如Bcl2）的成瘾。第三，我们已经建立了广泛表征了PTCL的体外和体内模型。其中包括> 30个患者来源带有特定区室特异性的10种不同PTCL亚型的异种移植物（PDX）和转基因小鼠 PTCL相关翻译的表达。第四，我们已经使用PDX模型执行了II期样的pre- MDM2抑制作用的临床试验，生成预测性生物标志物并定义获得的机制在体内药物治疗期间中继的PDX的体内耐药性。最后，我们证明了嵌合针对四跨果蛋白CD37（CART37）的抗原受体T细胞可以在体外放射PTCL细胞，并且体内。引人注目的是，CART37细胞不会引起替代性，杀死人髓样细胞或靶向非机敏的T细胞。我们的核心目标是制定知情策略，以改善PTCL患者的结果。有在项目1和2中概述的有希望的新方法，该方法阻断了基本信号传导或目标表观遗传缺陷。我们将与这些项目紧密合作，以定义良好特征的协同和对抗模型系统和主要样本（来自核心B）。获得体内抗性的模型将受到询问识别预测克服灵敏度和治疗方法的生物标志物（用核心C开发）阻力。目标1是定义结合针对针对的嵌合抗原受体T细胞的影响 CD37具有诱导PTCL凋亡的药物（MarkusMüschen/John Chan，项目1）。目标2是定义靶向PTCL特异性改变和凋亡的组合（与MarkusMüschen/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影响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PTCL患者的生物标志物驱动的人类研究。