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Role of IGF-IR tyrosine kinase in NPM-ALK-expressing T-cell lymphoma

IGF-IR 酪氨酸激酶在表达 NPM-ALK 的 T 细胞淋巴瘤中的作用

基本信息

批准号：
8680025
负责人：
HESHAM M AMIN
金额：
$ 31.8万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8680025
关键词：
2p23 5q35 ALK gene Accounting Affect Agar Age Amino Acids Apoptosis Binding Sites Biological Assay Bone Marrow Cell Cycle Arrest Cell Death Cell Line Cell Survival Cells Cessation of life Chemotherapy-Oncologic Procedure Child Chromosomal translocation Chromosomes Clinical Trials Collaborations Cyclophosphamide Data Defect Diagnosis Doxorubicin Event Feedback Gene Amplification Genes Goals Hematologic Neoplasms Hematopoietic Human In Vitro Insulin Receptor Insulin-Like Growth Factor Receptor Ki-1 Large-Cell Lymphoma Knockout Mice Lead Liver Lymph Node Involvement Lymphocyte Lymphoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of prostate Messenger RNA MicroRNAs Modality Molecular Non-Hodgkin&apos s Lymphoma Oncogenic Organ Outcome Pathway interactions Patients Phosphorylation Physiological Play Prednisone Protein Tyrosine Kinase Proteins Receptor Gene Receptor Protein-Tyrosine Kinases Receptor Signaling Regimen Relapse Reporter Genes Resistance Resistance development Role SCID Mice Signal Transduction Signaling Molecule Skin Solid Solid Neoplasm Specimen Staging T-Cell Lymphoma T-Lymphocyte Testing Therapeutic Transgenic Mice Type I Insulin Up-Regulation Vincristine Widespread Disease Xenograft procedure anaplastic lymphoma kinase base blastomere structure cytokine deletion analysis effective therapy in vivo inhibitor/antagonist insight insulin receptor tyrosine kinase mRNA Stability malignant breast neoplasm member metaplastic cell transformation multicatalytic endopeptidase complex mutant novel therapeutics nucleophosmin pre-clinical promoter receptor binding receptor expression receptor upregulation relating to nervous system research study response small molecule stable cell line success transcription factor treatment strategy young adult

项目摘要

DESCRIPTION (provided by applicant): Nucleophosmin-anaplastic lymphoma kinase-expressing anaplastic large-cell lymphoma (NPM-ALK+ ALCL) is an aggressive type of T-cell lymphoma. Although it occurs in patients of all ages, NPM-ALK+ ALCL is more frequently seen in young patients, accounting for 20-30% of non-Hodgkin's lymphomas in children and young adults. Patients typically present with advanced-stage disease and generalized involvement of the lymph nodes and other organs including skin, bone marrow, and liver. Currently, there is no effective treatment for this lymphoma, and as in other types of T-cell lymphoma, the treatment of NPM-ALK+ ALCL is primarily based on the CHOP combination chemotherapy regimen. After an initial favorable response to CHOP, up to 40% of NPM-ALK+ ALCL patients eventually have a relapse, develop resistance, and, in many cases, die. At the molecular level, NPM-ALK+ ALCL is characterized by the expression of the chimeric tyrosine kinase NPM-ALK, which induces significant oncogenic effects through interactions with downstream molecules that promote lymphoma cell survival. NPM-ALK is structurally similar to the type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase. IGF-IR plays important roles in promoting the survival of several solid tumors such as breast, prostate, lung, and ovarian cancers. Notably, several of the oncogenic molecules downstream of NPM-ALK also function downstream of IGF-IR. Nevertheless, whether IGF-IR has a functional role in NPM-ALK+ ALCL has not been examined. In preliminary studies we found that the expression of IGF-IR is upregulated in NPM-ALK+ ALCL cell lines compared with normal human T-cells. We also found that IGF-IR and NPM-ALK are physically associated and appear to interact through a reciprocal positive feedback loop to maintain their phosphorylation/ activation. An experimental inhibitor of IGF-IR induced apoptosis and cell cycle arrest and abrogated colony formation in soft agar of NPM-ALK+ ALCL cell lines. On the basis of these preliminary results, we hypothesize that upregulation of IGF-IR and its collaboration with NPM-ALK contribute to the survival of NPM-ALK+ ALCL and, therefore, targeting IGF-IR may be a reasonable strategy for treating this lymphoma. The specific aims of this proposal are as follows: 1. To identify the mechanisms by which IGF-IR expression is upregulated in NPM-ALK+ ALCL. 2. To characterize the interactions between IGF-IR and NPM-ALK in vitro and in vivo. 3. To examine the in vitro and in vivo preclinical effects of IGF-IR inhibitors currently being used in clinical trials in NPM-ALK+ ALCL. Our results will provide insight into the role of IGF-IR in NPM-ALK+ ALCL. Our long-term goal is to understand IGF-IR-dependent signaling in this aggressive lymphoma in order to devise novel therapeutic strategies. Tactics that antagonize IGF-IR could potentially provide a cure for NPM-ALK+ ALCL patients.

描述(申请人提供)：核磷蛋白间变性淋巴瘤-间变性大细胞淋巴瘤(NPM-ALK+ALCL)是一种侵袭性T细胞淋巴瘤。尽管NPM-ALK+ALCL可见于各个年龄段的患者，但以年轻人多见，占儿童和青壮年非霍奇金淋巴瘤的20-30%。患者通常表现为晚期疾病，广泛累及淋巴结和其他器官，包括皮肤、骨髓和肝脏。目前，这种淋巴瘤还没有有效的治疗方法，与其他类型的T细胞淋巴瘤一样，NPM-ALK+ALCL的治疗主要基于CHOP联合化疗方案。在最初对CHOP有良好的反应后，高达40%的NPM-ALK+ALCL患者最终复发，产生耐药性，在许多情况下，甚至死亡。在分子水平上，NPM-ALK+ALCL的特征是表达嵌合酪氨酸激酶NPM-ALK，它通过与促进淋巴瘤细胞存活的下游分子相互作用而诱导显著的致癌效应。NPM-ALK在结构上类似于I型胰岛素样生长因子受体(IGF-IR)酪氨酸激酶。IGF-IR在促进乳腺癌、前列腺癌、肺癌和卵巢癌等几种实体肿瘤的生存方面发挥着重要作用。值得注意的是，NPM-ALK下游的几个致癌分子也在IGF-IR下游发挥作用。然而，IGF-IR在NPM-ALK+ALCL中是否具有功能作用尚未得到研究。在初步研究中，我们发现与正常人T细胞相比，NPM-ALK+ALCL细胞系IGF-IR的表达上调。我们还发现，IGF-IR和NPM-ALK在物理上是相互关联的，并且似乎通过一个相互的正反馈环相互作用来维持它们的磷酸化/激活。一种实验性的IGF-IR抑制剂诱导NPM-ALK+ALCL细胞株在软琼脂中发生凋亡和细胞周期停滞，并抑制集落形成。在这些初步结果的基础上，我们假设IGF-IR的上调及其与NPM-ALK的协同作用有助于NPM-ALK+ALCL的生存，因此，靶向IGF-IR可能是治疗该淋巴瘤的合理策略。本研究的具体目的如下：1.明确NPM-ALK+ALCL中IGF-IR表达上调的机制。2.研究胰岛素样生长因子-IR与NPM-ALK在体内外的相互作用。3.检测目前用于NPM-ALK+ALCL临床试验的IGF-IR抑制剂的体内外临床前效应。我们的结果将为深入了解IGF-IR在NPM-ALK+ALCL中的作用提供依据。我们的长期目标是了解这种侵袭性淋巴瘤中的IGF-IR依赖信号，以便设计新的治疗策略。拮抗IGF-IR的策略可能为NPM-ALK+ALCL患者提供潜在的治愈方法。