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Mechanisms of sphingolipid analogue drug FTY720-mediated NSCLC tumor suppression

鞘脂类似物药物FTY720介导的NSCLC肿瘤抑制机制

基本信息

批准号：
9076632
负责人：
Besim Ogretmen
金额：
$ 31.02万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9076632
关键词：
BRAF gene Binding Biological Cancer Patient Cell Death Cell Nucleus Ceramides Cessation of life Clinical Data Development Disease Epidermal Growth Factor Receptor FDA approved Goals Growth Health Immune In Situ KRAS2 gene Lead Lung Malignant Neoplasms Mediating Molecular Molecular Target Multiple Sclerosis Mutation Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Patients Pharmaceutical Preparations Play Precision therapeutics Protein Phosphatase 2A Regulatory Subunit PR53 Publishing RIPK1 gene Refractory Regulation Role SET gene Signal Transduction Sphingolipids Sphingosine Stream Testing Tumor Suppression Tumor Suppressor Proteins Tumor Tissue United States analog base cancer cell design in vivo inhibitor/antagonist mimetics multiple sclerosis treatment new therapeutic target novel overexpression programs small molecule sphingosine kinase treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): FTY720 is a sphingosine analogue drug that has been recently approved by FDA for the treatment of patients with refractory multiple sclerosis (MS). FTY720 is phosphorylated by sphingosine kinase 2 (SK2), and P- FTY720 is immune suppressive, which is required for its anti-MS activity. This proposal was designed to test a novel hypothesis that FTY720, but not its immunesuppressive form P-FTY720, suppresses NSCLC tumor growth by directly targeting I2PP2A/SET oncoprotein, leading to activation of PP2A, RIPK1-dependent programmed necrosis (necroptosis) and consequent tumor suppression. To test this hypothesis, two Specific Aims are proposed: Aim 1 was designed to determine the roles and mechanisms by which binding I2PP2A/SET by FTY720 activates tumor suppressive PP2A. Aim 2 was designed to determine the down- stream mechanisms by which targeting I2PP2A/SET by FTY720 induces cell death.

描述（由申请人提供）：FTY 720是一种鞘氨醇类似物药物，最近已被FDA批准用于治疗难治性多发性硬化（MS）患者。FTY 720被鞘氨醇激酶2（SK 2）磷酸化，并且P-FTY 720是免疫抑制性的，这是其抗MS活性所需的。该提案旨在验证一个新假设，即FTY 720（而不是其免疫抑制形式P-FTY 720）通过直接靶向I2 PP 2A/SET癌蛋白来抑制NSCLC肿瘤生长，导致PP 2A、RIPK 1依赖性程序性坏死（坏死性凋亡）的激活并随之产生肿瘤抑制。为了验证这一假设，提出了两个特定的目的：目的1旨在确定FTY 720结合I2 PP 2A/SET激活肿瘤抑制性PP 2A的作用和机制。目的2：研究FTY 720靶向I2 PP 2A/SET诱导细胞死亡的下游机制。