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

• 批准号: 10518751
• 负责人: Lee Ratner
• 金额: $ 36.03万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10518751
• 关键词: Address; Adult T-Cell Leukemia/Lymphoma; Affect; Alleles; 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; Enrollment; 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; Lead; Lymphoma cell; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; Molecular; Monitor; Multi-Institutional Clinical Trial; Mus; Mutate; Mutation; Nuclear; PLC gamma1; Pathogenesis; Pathway interactions; Patients; Phase I Clinical Trials; Positioning Attribute; Prediction of Response to Therapy; 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; base; cell immortalization; chemotherapy; cytotoxic; experience; gain of function mutation; gene product; immunoregulation; improved; inhibitor; knock-down; lenalidomide; new therapeutic target; overexpression; phase 1 study; phase I trial; phospholipase C gamma; protein kinase C beta; recruit; response; small hairpin RNA; success; targeted treatment; therapeutic target; therapy resistant; transcription factor; transcriptome; transcriptome sequencing; tumorigenesis; ubiquitin-protein ligase

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.

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)是一种 侵袭性淋巴增生性恶性肿瘤。尽管进行了积极的化疗，但这种疾病在几乎所有人中都是致命的。 个人。我们和其他人的初步结果发现，T细胞受体的突变率很高 (Tcr)信号通路，磷脂酶Cγ、蛋白激酶Cβ(PKCβ)和 Caspase募集结构域包含蛋白11(CARD11)导致转录因子核激活 因子κB(NFκB)和干扰素调节因子4(IRF4)。我们假设这条路径驱动着ATL 针对这一途径的发展和/或进展和靶向治疗将与联合 化疗。我们还认为来那度胺抑制了ATLL中IRF4的表达。我们建议评估： 目的1：通过RNAseq研究IRF4激活在ATLL中的作用及对IRF4依赖基因的功能分析 目标。我们还将确定IRF4的抑制是否介导来那度胺对ATLL的细胞毒作用。 目的2：来那度胺联合新纪元化疗治疗HTLV-ATLL的1期研究 通过ETCTN进行的，以及在当前项目中进行的相关研究，以评估 来那度胺的疗效是通过对IRF4的影响而介导的，并依赖于TCR途径的突变 组件。HTLV的载量、表达和克隆性分析将用于监测治疗效果。 目的3：将pkcβ激活在atll中的作用作为替代治疗靶点进行研究。 ATLL细胞对抑制剂、苯扎他林和米多妥林的敏感性。我们将评估对这些问题的敏感性 抑制物受PKCβ或CARD11突变的影响，这两种突变经常在ATLL中共存。 这项研究将深入了解TCR信号在ATLL中的作用，并提供新的治疗靶点。