Inhibition of T-cell Receptor Signaling for Treatment of Adult T-cell Leukemia Lymphoma

抑制 T 细胞受体信号转导治疗成人 T 细胞白血病淋巴瘤

基本信息

批准号：
10684172
负责人：
Lee Ratner
金额：
$ 35.31万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684172
关键词：
Address Adult T-Cell Leukemia/Lymphoma Affect Alleles Angiogenesis Inhibitors Animal Model Antisense Oligonucleotides Antiviral Therapy Apoptosis Binding Biological Assay Biological Markers Bone Marrow CRISPR/Cas technology Caspase Cell Line Clinic Clinical Clinical Trials Network Clonality Clustered Regularly Interspaced Short Palindromic Repeats Combination Drug Therapy Correlative Study Development Disease Exons Gene Expression Gene Targeting Genes Genome Genotype Growth Human T-lymphotropic virus 1 IRF4 gene Imides Immune Immunodeficient Mouse Individual International Investigational Therapies Knock-out Knowledge Lymphoma cell Malignant Neoplasms Mature T-Lymphocyte Mediating Molecular Monitor Multi-Institutional Clinical Trial Mus Mutate Mutation Nuclear PLC gamma1 Pathogenesis Pathway interactions Phase I Clinical Trials Positioning Attribute Prediction of Response to Therapy Proliferating Protein Inhibition Proteins Receptor Signaling Refractory Registries Relapse Repression Role T Cell Receptor Signaling Pathway T-Cell Lymphoma T-Cell Receptor T-Cell and NK-Cell Neoplasm T-Lymphocyte Testing Therapeutic Transcriptional Activation Translating Transplantation Treatment Efficacy Validation Viral Genome Viral Oncogene Virus antitumor effect cell immortalization chemotherapy cytotoxic experience gain of function mutation gene product immunoregulation improved inhibitor knock-down lenalidomide leukemia/lymphoma new therapeutic target overexpression participant enrollment phase 1 study phase I trial phospholipase C gamma protein kinase C beta recruit response small hairpin RNA success synergism targeted treatment therapeutic target therapy resistant transcription factor transcriptome transcriptome sequencing tumorigenesis ubiquitin-protein ligase

项目摘要

Abstract – Inhibition of T-Cell Receptor Signaling for Treatment of Adult T-Cell Leukemia Lymphoma Human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia-lymphoma (ATLL) is an aggressive lymphoproliferative malignancy. Despite aggressive chemotherapy, this disorder is fatal in almost all individuals. Our preliminary results, and those of others, uncovered a high rate of mutations in the T-cell receptor (TCR) signaling pathway in ATLL, with frequent mutations in phospholipase Cγ, protein kinase Cβ (PKCβ), and caspase recruitment domain containing protein 11 (CARD11) leading to activation of transcription factors nuclear factor κB (NFκB) and interferon-regulatory factor 4 (IRF4). We hypothesize that this pathway drives ATLL development and/or progression and targeted therapy against this pathway will synergize with combination chemotherapy. We also suggest that lenalidomide represses IRF4 expression in ATLL. We propose to assess: Aim 1: Role of IRF4 activation in ATLL through RNAseq and functional analysis of IRF4-dependent gene targets. We will also determine if repression of IRF4 mediates the cytotoxic effects of lenalidomide in ATLL. Aim 2: Phase 1 study of lenalidomide in combination with EPOCH chemotherapy for HTLV-ATLL is conducted through the ETCTN, and correlative studies performed in the current project to assess whether efficacy of lenalidomide is mediated through effects on IRF4, and depend on mutations in TCR pathway components. HTLV load, expression, and clonality assays will be used to monitor the efficacy of therapy. Aim 3: Role of PKCβ activation in ATLL will be examined as an alternative therapeutic target, based on sensitivity of ATLL cells to inhibitors, enzastaurin and midostaurin. We will assess whether sensitivity to these inhibitors are affected by mutations in PKCβ or CARD11, which often co-occur in ATLL. This study will provide in-depth knowledge of the role of TCR signaling in ATLL, and new therapeutic targets.

摘要 – 抑制 T 细胞受体信号转导治疗成人 T 细胞白血病淋巴瘤人类 T 细胞白血病病毒 1 型 (HTLV-1) 相关成人 T 细胞白血病淋巴瘤 (ATLL) 是一种尽管进行了积极的化疗，这种疾病对几乎所有疾病都是致命的。我们和其他人的初步结果发现，T 细胞受体的突变率很高。 ATLL 中的 (TCR) 信号通路，磷脂酶 Cγ、蛋白激酶 Cβ (PKCβ) 和蛋白激酶 Cβ 频繁突变含有蛋白 11 (CARD11) 的 caspase 募集结构域导致核转录因子激活我们发现该通路驱动 ATLL。发展和/或进展以及针对该途径的靶向治疗将与组合产生协同作用我们还建议来那度胺抑制 ATLL 中的 IRF4 表达。目标 1：通过 RNAseq 和 IRF4 依赖性基因的功能分析来了解 IRF4 激活在 ATLL 中的作用我们还将确定 IRF4 的抑制是否介导来那度胺在 ATLL 中的细胞毒性作用。目标 2：来那度胺联合 EPOCH 化疗治疗 HTLV-ATLL 的 1 期研究正在进行通过 ETTCTN 进行，并在当前项目中进行相关研究，以评估是否来那度胺的功效是通过对 IRF4 的影响介导的，并且取决于 TCR 通路的突变 HTLV 负载、表达和克隆性测定将用于监测治疗效果。目标 3：将检查 PKCβ 激活在 ATLL 中的作用，作为替代治疗靶点，基于 ATLL 细胞对抑制剂 enzastaurin 和 midostaurin 的敏感性我们将评估是否对这些抑制剂敏感。抑制剂受到 PKCβ 或 CARD11 突变的影响，这些突变通常在 ATLL 中同时发生。这项研究将深入了解 TCR 信号传导在 ATLL 中的作用以及新的治疗靶点。