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细胞受体信号用于治疗成人T细胞白血病淋巴瘤人类T细胞白血病病毒1型（HTLV-1）相关的成人T细胞白血病 - 淋巴瘤（ATLL）是侵略性淋巴增生性恶性肿瘤。尽管进行了积极的化学疗法，但这种疾病几乎全部致命个人。我们的初步结果以及其他结果，发现了T细胞接收器中的高突变率（TCR）ATLL中的信号通路，在磷脂酶Cγ，蛋白激酶Cβ（PKCβ）和 caspase募集结构域含有蛋白质11（card11），导致转录因子的激活核因子κB（NFκB）和干扰素调节因子4（IRF4）。我们假设该途径驱动ATLL 开发和/或进展以及针对该途径的靶向疗法将与组合协同化学疗法。我们还建议，来那捷胺反映了ATLL中的IRF4表达。我们建议评估： AIM 1：IRF4激活在ATLL中的作用通过RNASEQ和IRF4依赖性基因的功能分析目标。我们还将确定IRF4的表达是否介导了Lenalidomide在ATLL中的细胞毒性作用。 AIM 2：Lenalidomide与HTLV-ATLL时期化学疗法结合的1阶段研究通过ETCTN进行的，并在当前项目中进行的正确研究，以评估是否是否 Lenalidomide的作用是通过对IRF4的影响介导的，并取决于TCR途径中的突变成分。 HTLV负载，表达和克隆性测定将用于监测治疗的效率。目标3：基于 ATLL细胞对抑制剂，Enzastaurin和Midostaurin的敏感性。我们将评估对这些的敏感性抑制剂受PKCβ或Card11突变的影响，这些突变通常在ATLL中共发生。这项研究将对TCR信号在ATLL和新的治疗靶标的作用提供深入的了解。