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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：
7800291
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 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7800291
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（由申请人提供）：肺癌早期检测的困难、其侵袭性、缺乏有效的全身治疗以及对化疗药物的快速耐药性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。通过基因转移恢复肿瘤抑制和凋亡途径中缺陷基因和基因产物的功能，并通过“智能药物”（如蛋白酪氨酸激酶（PTK）抑制剂）靶向关键信号传导途径中特异性和频繁发生的分子改变的新治疗方法，正在从根本上改变癌症治疗，并为肺癌治疗带来希望。我们的目标是通过使用DOTAP结合全身性和肿瘤选择性分子治疗来开发恶性肺癌和转移的综合治疗策略：胆固醇-DNA纳米颗粒，其具有由嵌合hTERT-mini-CMV（hTMC）启动子驱动的新型多功能肿瘤抑制基因FUS 1以直接激活凋亡途径，使用小分子PTK抑制剂特异性靶向致癌PTK介导的信号传导途径的化疗策略，以及创新的，使用hTMC-SSRT 2A-FUS 1载体系统的非侵入性分子成像技术与磁共振成像和γ-照相机成像以监测治疗基因的表达和抗癌功效。该目标将通过以下具体目的实现：1）评估hTMC-FUS 1纳米颗粒在人肺癌小鼠模型中全身给药的治疗功效; 2）评估FUS 1纳米颗粒和新型小分子PTK抑制剂厄洛替尼和伊马替尼在体外和体内治疗以增强功效和克服肺癌耐药性的治疗功效; 3）分析FUS 1蛋白与其在肿瘤抑制、凋亡和PTK信号通路中的细胞靶点的相互作用，以揭示FUS 1介导的肿瘤抑制的分子机制并鉴定潜在的治疗靶点;和4）在小鼠中开发非侵入性分子成像技术，用于使用hTMC-FUS 1-SSRT 2A双报告基因和治疗性基因表达系统，通过γ照相机成像，并通过磁共振成像分析评估FUS 1-纳米颗粒的全身治疗效果。