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Tumor and PTK-Targeted Therapy by FUS1 and PTK inhibitor

FUS1和PTK抑制剂的肿瘤和PTK靶向治疗

基本信息

批准号：
7623503
负责人：
LIN JI
金额：
$ 29.26万
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：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7623503
关键词：
3p21.3 ABL1 gene Adverse effects Animal Model Animals Apoptosis Apoptotic Automobile Driving Biochemical Biodistribution CMV promoter Cancer Center Cancer Etiology Cell Cycle Kinetics Cell Death Signaling Process Cells Cessation of life Cholesterol Chromosomes Complement Complex Core Facility Cytomegalovirus DNA Development Diagnostic radiologic examination Disease Doctor of Philosophy Dose Drug resistance Epidermal Growth Factor Receptor Erlotinib FDA approved Gefitinib Gene Expression Gene Expression Profiling Gene Transduction Agent Gene Transfer Gene-Modified Genes Gleevec Goals Growth Hand Human Image Image Analysis Imaging Techniques Imaging technology Imatinib In Vitro Indium Induction of Apoptosis Inherited Laboratories Lead Lung Lung Neoplasms Magnetic Resonance Imaging Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mathematics Measures Mediating Mediator of activation protein Methods Minority Molecular Monitor Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Octreotide Oncogenes Oncogenic Organ PDAP2 Gene PDGFRB gene Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Phosphorylation Population Principal Investigator Property Protein Tyrosine Kinase Proteins Proteomics Proto-Oncogene Protein c-kit Radionuclide Imaging Reporter Reporter Genes Research Personnel Resistance Resistance development Role SSTR2A STI571 Signal Pathway Signal Transduction Silicon Dioxide Site Spatial Distribution Staging Statistical Models Survival Rate System Systemic Therapy Technology Testing Therapeutic Therapeutic Effect Toxic effect Transgenes Treatment Efficacy Tumor Suppression Tumor Suppressor Genes Tumor Tissue Tyrosine Kinase Inhibitor United States Vertebral column Woman Work Xenograft Model apoptotic protease-activating factor 1 base c-abl Proto-Oncogenes cancer cell cancer therapy cell growth cellular targeting chemotherapeutic agent chemotherapy design expression vector functional restoration gene therapy gene therapy clinical trial human TERT protein immunogenic improved in vivo innovation insight killings lung small cell carcinoma malignant breast neoplasm molecular imaging mortality mouse model nanoparticle neoplastic cell novel novel therapeutics programs promoter protein protein interaction response selective expression small molecule somatostatin receptor 2 synergism therapeutic gene therapeutic target therapy design tool treatment strategy tumor tumor growth tumor xenograft vector vector-induced

项目摘要

DESCRIPTION (provided by applicant): The difficulty of detecting lung cancer at an early stage, its aggressiveness, the lack of effective systemic therapy, and the rapid development of resistance to chemotherapeutics are responsible for its high mortality. There is an urgent need for novel therapeutic strategies for the efficient treatment of lung cancer and new ways to overcome drug resistance. New treatments designed to restore functions of defective genes and gene products in tumor suppressing and apoptotic pathways by gene transfer and to target specific and frequently occurring molecular alterations in key signaling pathways by "smart drugs," such as protein tyrosine kinase (PTK) inhibitors, are fundamentally changing cancer therapy and hold promise for lung cancer treatment. Our goal is to develop an integrated therapeutic strategy for malignant lung cancer and metastases by combining a systemic and tumor-selective molecular therapy using DOTAP:Cholesterol-DNA nanoparticles with the novel multifunctional tumor suppressor gene FUS1 driven by a chimeric hTERT-mini-CMV (hTMC) promoter to directly activate the apoptotic pathway, a chemotherapy strategy using small molecule PTK inhibitors to specifically target the oncogenic PTK-mediated signaling pathway, and an innovative, noninvasive molecular imaging technique using an hTMC-SSRT2A-FUS1 vector system with magnetic resonance imaging and gamma-camera imaging to monitor the expression and anticancer efficacy of the therapeutic gene. This goal will be achieved via these Specific Aims: 1) evaluating the therapeutic efficacy of systemic administration of hTMC-FUS1 nanoparticles in human lung cancer mouse models; 2) evaluating the therapeutic efficacy of treatment with FUS1 nanoparticles and novel small molecule PTK inhibitors erlotinib and imatinib in vitro and in vivo to enhance efficacy and overcome drug resistance in lung cancer; 3) analyzing the interactions of the Fus1 protein with its cellular targets in tumor suppressing, apoptotic, and PTK signaling pathways to reveal the molecular mechanisms of FUS1-mediated tumor suppression and identify potential therapeutic targets; and 4) developing noninvasive molecular imaging technologies in mice for monitoring gene expression and biodistribution using the hTMC-FUS1-SSRT2A dual reporter and therapeutic gene expression system by gamma-camera imaging and for evaluation of the systemic therapeutic efficacy of FUS1-nanoparticles by magnetic resonance imaging analysis.

描述（申请人提供）：肺癌早期检测困难、侵袭性强、缺乏有效的全身治疗以及化疗耐药性的迅速发展是其高死亡率的原因。迫切需要有效治疗肺癌的新治疗策略和克服耐药性的新方法。新疗法旨在通过基因转移恢复肿瘤抑制和细胞凋亡途径中缺陷基因和基因产物的功能，并通过蛋白酪氨酸激酶（PTK）抑制剂等“智能药物”针对关键信号传导途径中特定且频繁发生的分子改变，这些新疗法正在从根本上改变癌症疗法，并为肺癌治疗带来希望。我们的目标是开发一种针对恶性肺癌和转移瘤的综合治疗策略，将使用 DOTAP:胆固醇-DNA 纳米粒子的系统性和肿瘤选择性分子疗法与由嵌合 hTERT-mini-CMV (hTMC) 启动子驱动的新型多功能肿瘤抑制基因 FUS1 相结合，直接激活细胞凋亡途径，这是一种使用小分子的化疗策略。分子 PTK 抑制剂专门针对致癌 PTK 介导的信号通路，以及一种创新的非侵入性分子成像技术，使用 hTMC-SSRT2A-FUS1 载体系统，通过磁共振成像和伽马相机成像来监测治疗基因的表达和抗癌功效。这一目标将通过以下具体目标来实现：1) 评估 hTMC-FUS1 纳米颗粒在人肺癌小鼠模型中全身给药的治疗效果； 2）评估FUS1纳米颗粒与新型小分子PTK抑制剂埃罗替尼和伊马替尼在体外和体内的治疗效果，以增强肺癌疗效并克服耐药性； 3）分析Fus1蛋白与其在肿瘤抑制、细胞凋亡和PTK信号通路中的细胞靶点的相互作用，揭示FUS1介导的肿瘤抑制的分子机制并识别潜在的治疗靶点； 4) 开发小鼠无创分子成像技术，通过伽玛相机成像使用 hTMC-FUS1-SSRT2A 双报告基因和治疗基因表达系统监测基因表达和生物分布，并通过磁共振成像分析评估 FUS1 纳米粒子的全身治疗功效。