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

• 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
• 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' 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

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（由申请方提供）：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T细胞淋巴瘤。虽然它发生在所有年龄段的患者中，但NPM-ALK+ ALCL更常见于年轻患者，占儿童和年轻成人非霍奇金淋巴瘤的20-30%。患者通常表现为晚期疾病和淋巴结和其他器官（包括皮肤、骨髓和肝脏）的全身受累。目前，这种淋巴瘤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。在对CHOP的初始良好反应后，高达40%的NPM-ALK+ ALCL患者最终复发，产生耐药性，并且在许多情况下死亡。在分子水平上，NPM-ALK+ ALCL的特征在于表达嵌合酪氨酸激酶NPM-ALK，其通过与促进淋巴瘤细胞存活的下游分子相互作用诱导显著的致癌效应。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在促进几种实体瘤如乳腺癌、前列腺癌、肺癌和卵巢癌的存活中起重要作用。值得注意的是，NPM-ALK下游的几种致癌分子也在IGF-IR下游发挥作用。然而，IGF-IR是否在NPM-ALK+ ALCL中发挥功能性作用尚未研究。在初步研究中，我们发现与正常人T细胞相比，NPM-ALK+ ALCL细胞系中IGF-IR的表达上调。我们还发现IGF-IR和NPM-ALK在物理上相关，似乎通过相互的正反馈回路相互作用，以维持其磷酸化/激活。在NPM-ALK+ ALCL细胞系的软琼脂中，一种实验性IGF-IR抑制剂可诱导细胞凋亡和细胞周期阻滞，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的生存，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.描述IGF-IR和NPM-ALK在体外和体内的相互作用。 3.检查目前在NPM-ALK+ ALCL临床试验中使用的IGF-IR抑制剂的体外和体内临床前作用。我们的研究结果将为深入了解IGF-IR在NPM-ALK+ ALCL中的作用提供帮助。我们的长期目标是了解这种侵袭性淋巴瘤的IGF-IR依赖性信号转导，以设计新的治疗策略。拮抗IGF-IR的策略可能为NPM-ALK+ ALCL患者提供治愈。