Systemic Non-Viral Gene Therapy for Cancer

描述（由申请人提供）：肺癌是世界上癌症相关死亡的主要原因，主要死因是肿瘤转移。由于无法控制肿瘤的局部扩散以及无法治疗远处转移性肿瘤，患者经常复发，导致对治疗的抵抗。因此，需要新的治疗方式。最近显示出希望的一种治疗方法是基因疗法。虽然腺病毒介导的基因转移治疗癌症已显示出临床前景，但由于毒性和免疫反应，其使用仅限于局部区域治疗。我们设想的另一种治疗策略是将包裹在非病毒载体中的新型肿瘤抑制基因全身递送，这种载体不仅免疫原性较低，而且可以有效地将治疗基因递送到原发性和转移性肿瘤。我们实验室和其他实验室的临床前研究表明，DOTAP：胆固醇（DOTAP:Chol）脂质体是一种有效的载体，可将治疗性基因系统递送到动物的原发性和实验性转移性肿瘤中，从而抑制肿瘤并延长动物的生存期。基于我们的临床前研究，我们已经启动了晚期化疗难治性非小细胞肺癌的第一个系统性I期癌症基因治疗临床试验，其中肿瘤抑制基因（Fus1）包封在DOTAP:Chol中。脂质体（脂质体）是全身给药。在目前的提案中，我们计划进行额外的临床前研究并获得新的信息，以促进我们对载体介导的炎症反应的作用的理解；开发绕过主机响应的方法；并研究小分子抑制剂对治疗效果和抑制载体介导的炎症反应的影响。为此，我们确定了三个具体目标：目的1：研究脂质体介导的荷瘤小鼠和非荷瘤小鼠的炎症反应。目的2：建立脂质体诱导炎症反应的机制。目的3：制定克服脂质体介导的炎症反应的策略，并在体内测量治疗效果。在本应用程序中提出的具体目标将通过利用分子，细胞和动物模型来实现。从拟议的研究中产生的研究结果将对临床转化很重要，并将立即应用于目前的临床试验和未来临床试验的设计。公共卫生相关性：该提案的主要目标是开发一种有效的系统性非病毒基因传递系统，用于治疗肺癌。在目前的建议中，我们计划研究炎症反应的分子机制，并制定策略来克服媒介诱导的炎症反应，使用体外和体内模型。我们的研究将为肺癌治疗和临床应用提供一种改进的全身基因传递载体。

DESCRIPTION (provided by applicant): Lung cancer is a major cause of cancer-related mortality in the world with the primary cause of death being from tumor metastases. Due to the inability to control local tumor spread as well as failure to treat metastatic tumors at distant sites, patients often relapse resulting in resistance to treatment. Therefore, novel forms of treatment modalities are mandated. One therapeutic approach that has shown recent promise is gene therapy. Although adenovirus-mediated gene transfer for treatment of cancer has shown clinical promise, its use has been limited to loco-regional treatment owing to toxicity and immune response. An alternate treatment strategy we envision is the systemic delivery of novel tumor suppressor genes encapsulated in a non-viral vector that not only are less immunogenic but can effectively deliver therapeutic genes to both primary and metastatic tumor. Preclinical studies from our laboratory and others have demonstrated DOTAP:Cholesterol (DOTAP:Chol) liposome to be an efficient vector for systemic delivery of therapeutic genes to primary and experimental metastatic tumors in animals, resulting in tumor suppression and prolonged animal survival. Based on our preclinical studies we have initiated the first systemic Phase I cancer gene therapy clinical trial for advanced chemotherapy refractory non-small cell lung cancer where a tumor suppressor gene (Fus1) encapsulated in DOTAP:Chol. liposome (lipoplex) is administered systemically. We, in the present proposal, plan to conduct additional preclinical studies and obtain new information to advance our understanding on the role of vector-mediated inflammatory response; develop methods to circumvent the host-response; and study the effects of small molecule inhibitors on therapeutic efficacy and on suppressing vector-mediated inflammatory response. For this purpose we have identified three specific aims: Aim 1: Study the lipoplex-mediated inflammatory response in tumor-bearing and non tumor-bearing mice. Aim 2: Establish the mechanism of induction of inflammatory response by lipoplex. Aim 3: Develop strategies to overcome the lipoplex-mediated inflammatory response and measure the therapeutic efficacy in vivo. The goals of the specific aims proposed in this application will be achieved by utilizing molecular, cellular and animal models. The research findings generated from the proposed studies will be important for clinical translation and will have immediate application in the clinic for the present trial and in the design of future clinical trials. PUBLIC HEALTH RELEVANCE: The major goal of the proposal is to develop an efficient systemic non-viral gene delivery system for treatment of lung cancer. In the present proposal we plan to study the molecular mechanism of inflammatory response as well as develop strategies to overcome the vector-induced inflammatory response using in vitro and in vivo models. Our studies will lead to an improved systemic gene delivery vehicle for lung cancer therapy and its application in the clinic.