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，主要死亡原因是肿瘤转移。由于无法控制局部肿瘤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，新形式的治疗模式是强制性的。最近显示出希望的一种治疗方法是基因治疗。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封装在非病毒载体中的新型肿瘤抑制基因全身递送，所述非病毒载体不仅免疫原性较低，而且可以有效地将治疗基因递送至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，可将治疗性基因全身递送至动物的原发性和实验性转移性肿瘤，从而抑制肿瘤并延长动物生存期。基于我们的临床前研究，我们已经启动了针对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（Fus 1）封装在DOTAP：Chol中。脂质体（lipoplex）是全身给药的。在本提案中，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;开发规避宿主反应的方法;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的目标：目标1：研究脂质复合物介导的炎症反应在荷瘤和非荷瘤小鼠。目的2：探讨Lipoplex诱导炎症反应的机制。目的3：开发克服脂质复合物介导的炎症反应的策略并测量体内治疗效果。本申请中提出的具体目的的目标将通过利用分子、细胞和动物模型来实现。从拟定研究中获得的研究结果对于临床转化非常重要，并将立即应用于当前试验的临床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递送系统用于治疗肺癌。在目前的建议中，我们计划研究炎症反应的分子机制，以及开发策略，以克服载体诱导的炎症反应，在体外和体内模型。我们的研究将为肺癌治疗提供一种更好的系统性基因载体，并将其应用于临床。

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.