Tumor and PTK-Targeted Therapy by FUS1 and PTK inhibitor

描述（申请人提供）：肺癌的早期发现困难，其侵袭性，缺乏有效的全身治疗，以及对化疗药物的耐药性的迅速发展是其高死亡率的原因。为了有效地治疗肺癌，迫切需要新的治疗策略和克服耐药性的新方法。新的治疗方法旨在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）靶向关键信号通路中特异性和频繁发生的分子改变，从根本上改变癌症治疗方法，并有望用于肺癌治疗。我们的目标是通过将DOTAP：胆固醇- dna纳米颗粒与新型多功能肿瘤抑制基因FUS1（由嵌合hTERT-mini-CMV （hTMC）启动子驱动，直接激活凋亡途径）结合起来，开发一种针对恶性肺癌和转移瘤的综合治疗策略，一种使用小分子PTK抑制剂特异性靶向PTK介导的致癌信号通路的化疗策略。利用hTMC-SSRT2A-FUS1载体系统，结合磁共振成像和伽马相机成像技术，创新的无创分子成像技术，监测治疗基因的表达和抗癌效果。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的治疗效果；2)评价FUS1纳米颗粒与新型PTK小分子抑制剂厄洛替尼、伊马替尼治疗肺癌的体内外疗效，增强疗效，克服耐药；3)分析Fus1蛋白与细胞靶点在肿瘤抑制、凋亡和PTK信号通路中的相互作用，揭示Fus1介导的肿瘤抑制的分子机制，发现潜在的治疗靶点；4)开发无创分子成像技术，利用伽马相机成像技术监测小鼠hTMC-FUS1-SSRT2A双报告和治疗基因表达系统的基因表达和生物分布，并通过磁共振成像分析评估fus1纳米颗粒的全身治疗效果。

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.