Dysregulation of STAT3 in ALK-induced oncogenesis

ALK 诱导的肿瘤发生中 STAT3 的失调

• 批准号: 6604201
• 负责人: MARIUSZ A. WASIK
• 金额: $ 30.12万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6604201
• 关键词: SCID mouse; antineoplastics; biological signal transduction; carcinogenesis; clinical research; human tissue; lymphoma; microarray technology; molecular oncology; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; protein tyrosine kinase; transcription factor

DESCRIPTION (provided by the applicant): This proposal is aimed at understanding mechanisms of malignant transformation mediated by an oncogenic anaplastic large cell lymphoma kinase (ALK) found so far to be expressed in the subset of human T/null-cell lymphomas (ALK¿ TCL), rhabdomyosarcomas, neuroblastomas, and inflammatory myofibroblastic tumors. Whereas ALK is capable of transforming lymphoid cells, the mechanisms of ALK-mediated oncogenesis remain mostly unknown. In this study we will determine the role of STAT3 and STAT3 regulatory and effector proteins in the ALK-mediated oncogenesis and establish preclinical model aimed at development of novel treatment for ALK+ TCL based on targeting ALK/STAT-related cell signaling. To accomplish this goal we will: 1 examine the prevalence and oncogenic consequences of the STAT3 activation in ALK+ TCL.2. define the role of negative regulators of STAT3 activation (PIAS3, SOCS3, and SHIP-i) in the ALK+ TCL pathogenesis and explore the mechanisms that control their expression and function.3 identify and determine the role in ALK+ TCL pathogenesis of the down-stream effectors of STAT3 by examining the expression and function of genes known to be regulated by STAT3 and potential novel STAT3 target genes using cDNA microarray technology.4. determine the in vitro and in vivo effects on ALK+TCL cells of drug combinations that include ALK inhibitor, STAT3 antisense oligonucleotide, mTOR kinase inhibitor, PP2A inhibitor, and/or DNA methylation inhibitor/SHP- 1 phosphatase inducer. This study should result in a better understanding of the pathogenesis of ALK+ TCL and may lead to novel therapies for this type of lymphoma based on selective inhibition of the cell signaling mediated by ALK, STAT3 and STAT3-regulatory molecules different from ALK. Because aberrant STAT3 signaling emerges as a critical factor in the pathogenesis of various types of hematopoietic and non-hematopoietic tumors and aberrant ALK expression is not limited only to the ALK¿ TCL, results of this study may impact on understanding pathogenesis and treatment of broad spectrum of malignancies.

描述（由申请方提供）：本提案旨在了解由致癌性间变性大细胞淋巴瘤激酶（ALK）介导的恶性转化机制，迄今为止发现该激酶在人T/裸细胞淋巴瘤（ALK <$TCL）、横纹肌肉瘤、神经母细胞瘤和炎性肌纤维母细胞瘤亚群中表达。尽管ALK能够转化淋巴样细胞，但ALK介导的肿瘤发生机制仍不清楚。在本研究中，我们将确定STAT 3和STAT 3调节和效应蛋白在ALK介导的肿瘤发生中的作用，并建立临床前模型，旨在开发基于靶向ALK/STAT相关细胞信号传导的ALK+ TCL新治疗方法。为实现这一目标，我们将： 1检查ALK+ TCL中STAT 3激活的患病率和致癌后果。定义STAT 3激活的负调节因子的作用（PIAS 3，SOCS 3，和SHIP-i）在ALK+ TCL发病机制中的作用，并探索控制其表达和功能的机制。通过使用cDNA微阵列检测已知受STAT 3调节的基因和潜在的新型STAT 3靶基因的表达和功能，技术。确定包括ALK抑制剂、STAT 3反义寡核苷酸、mTOR激酶抑制剂、PP 2A抑制剂和/或DNA甲基化抑制剂/SHP- 1磷酸酶诱导剂的药物组合对ALK+TCL细胞的体外和体内作用。 这项研究应该能够更好地了解ALK+ TCL的发病机制，并可能基于选择性抑制ALK、STAT 3和与ALK不同的STAT 3调节分子介导的细胞信号传导，为此类淋巴瘤提供新的治疗方法。由于异常STAT 3信号传导是各种类型造血和非造血肿瘤发病机制中的关键因素，并且异常ALK表达不仅限于ALK <$TCL，因此本研究的结果可能会影响对广谱恶性肿瘤发病机制和治疗的理解。