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：
8847660
负责人：
HESHAM M AMIN
金额：
$ 32.79万
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8847660
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（由申请人提供）：表达核磷蛋白-间变性淋巴瘤激酶的间变性大细胞淋巴瘤（NPM-ALK+ ALCL）是一种侵袭性类型的 T 细胞淋巴瘤。尽管发生于所有年龄段的患者，但 NPM-ALK+ ALCL 更常见于年轻患者，占儿童和年轻人非霍奇金淋巴瘤的 20-30%。患者通常表现为晚期疾病，淋巴结和其他器官（包括皮肤、骨髓和肝脏）广泛受累。目前，该淋巴瘤尚无有效治疗方法，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。在对 CHOP 产生初步良好反应后，高达 40% 的 NPM-ALK+ ALCL 患者最终会出现复发、产生耐药性，并且在许多情况下死亡。在分子水平上，NPM-ALK+ ALCL 的特点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，诱导显着的致癌作用。 NPM-ALK 在结构上与 I 型胰岛素样生长因子受体 (IGF-IR) 酪氨酸激酶相似。 IGF-IR 在促进乳腺癌、前列腺癌、肺癌和卵巢癌等多种实体瘤的存活中发挥着重要作用。值得注意的是，NPM-ALK 下游的一些致癌分子也在 IGF-IR 下游发挥作用。然而，IGF-IR 是否在 NPM-ALK+ ALCL 中具有功能作用尚未得到检验。在初步研究中，我们发现与正常人 T 细胞相比，NPM-ALK+ ALCL 细胞系中 IGF-IR 的表达上调。我们还发现 IGF-IR 和 NPM-ALK 在物理上相关，并且似乎通过相互正反馈回路相互作用以维持其磷酸化/激活。 IGF-IR 的实验性抑制剂可诱导 NPM-ALK+ ALCL 细胞系软琼脂中的细胞凋亡和细胞周期停滞，并消除集落形成。基于这些初步结果，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 的存活，因此，靶向 IGF-IR 可能是治疗这种淋巴瘤的合理策略。本提案的具体目标如下： 1. 确定 NPM-ALK+ ALCL 中 IGF-IR 表达上调的机制。 2. 表征IGF-IR和NPM-ALK在体外和体内的相互作用。 3. 检验目前用于 NPM-ALK+ ALCL 临床试验的 IGF-IR 抑制剂的体外和体内临床前效果。我们的结果将深入了解 IGF-IR 在 NPM-ALK+ ALCL 中的作用。我们的长期目标是了解这种侵袭性淋巴瘤中 IGF-IR 依赖性信号传导，以便设计新的治疗策略。拮抗 IGF-IR 的策略可能为 NPM-ALK+ ALCL 患者提供治愈方法。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Validation of a Preclinical Model of Diethylnitrosamine-Induced Hepatic Neoplasia in Yucatan Miniature Pigs.

尤卡坦小型猪二乙基亚硝胺诱导的肝肿瘤临床前模型的验证。

DOI：
发表时间：
2016
期刊：
影响因子：
3.5
作者：
Mitchell, Jennifer;Tinkey, Peggy T;Avritscher, Rony;Van Pelt, Carolyn;Eskandari, Ghazaleh;Konnath George, Suraj;Xiao, Lianchun;Cressman, Erik;Morris, Jeffrey S;Rashid, Asif;Kaseb, Ahmed O;Amin, Hesham M;Uthamanthil, Rajesh
通讯作者：
Uthamanthil, Rajesh

Dual inhibition of IGF-IR and ALK as an effective strategy to eradicate NPM-ALK+ T-cell lymphoma.

IGF-IR 和 ALK 的双重抑制是根除 NPM-ALK T 细胞淋巴瘤的有效策略。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
George, Bhawana;George, Suraj Konnath;Shi, Wenyu;Haque, Abedul;Shi, Ping;Eskandari, Ghazaleh;Axelson, Magnus;Larsson, Olle;Kaseb, Ahmed O;Amin, Hesham M
通讯作者：
Amin, Hesham M

3D tissue-engineered model of Ewing's sarcoma.

尤文肉瘤的 3D 组织工程模型。

DOI：
发表时间：
2014-12-15
期刊：
影响因子：
16.1
作者：
Lamhamedi;Santoro, Marco;Ramammoorthy, Vandhana;Menegaz, Brian A;Bartholomeusz, Geoffrey;Iles, Lakesla R;Amin, Hesham M;Livingston, J Andrew;Mikos, Antonios G;Ludwig, Joseph A
通讯作者：
Ludwig, Joseph A

Targeting Notch1 and proteasome as an effective strategy to suppress T-cell lymphoproliferative neoplasms.

靶向 Notch1 和蛋白酶体是抑制 T 细胞淋巴增殖性肿瘤的有效策略。

DOI：
发表时间：
2015-06-20
期刊：
影响因子：
0
作者：
Yang, Lujun;Zhang, Shuangfeng;George, Suraj Konnath;Teng, Rong;You, Xuefen;Xu, Mengqi;Liu, Hong;Sun, Xiaoping;Amin, Hesham M;Shi, Wenyu
通讯作者：
Shi, Wenyu

IGF-1R and mTOR Blockade: Novel Resistance Mechanisms and Synergistic Drug Combinations for Ewing Sarcoma.

IGF-1R 和 mTOR 阻断：尤文肉瘤的新型耐药机制和协同药物组合。

DOI：
10.1093/jnci/djw182
发表时间：
2016-12-01
期刊：
Journal of the National Cancer Institute
影响因子：
0
作者：
S. Lamhamedi;Brian A. Menegaz;V. Ramamoorthy;Deeksha Vishwamitra;Ying Wang;Rebecca L. Maywald;Adriana S Buford;I. Fokt;S. Skóra;Jing Wang;A. Naing;A. Lazar;E. Rohren;N. Daw;V. Subbiah;R. Benjamin;R. Ratan;W. Priebe;A. Mikos;H. Amin;J. Ludwig
通讯作者：
J. Ludwig