Image Based Evaluation of Tumor Targeting and Efficacy of Gene Therapy

基于图像的肿瘤靶向和基因治疗疗效评估

• 批准号: 7759151
• 负责人: VIKAS KUNDRA
• 金额: $ 16.94万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-16 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7759151
• 关键词: Address; Affect; Anatomy; Apoptosis; Biopsy; Cardiovascular Diseases; Cells; Chimera organism; Diabetes Mellitus; Disadvantaged; Disease; Dose; Effectiveness; Evaluation; FDA approved; Gene Expression; Gene Transfer; Gene Transfer Techniques; Genes; Genetic Transcription; Growth; Growth Inhibitors; Hereditary Disease; Human; Image; Imaging Techniques; Light; Link; Location; Luciferases; Malignant Neoplasms; Methods; Modeling; Monitor; Neurodegenerative Disorders; Normal Cell; Normal tissue morphology; Octreotide; Radiopharmaceuticals; Receptor Gene; Regimen; Reporter; Reporter Genes; SSTR2A; Signal Transduction; Somatostatin Receptor; System; Telomerase; Testing; Therapeutic; Tissues; Toxic effect; base; cancer therapy; design; gene therapy; human TERT protein; human tissue; in vivo; infancy; interest; pre-clinical; promoter; public health relevance; reproductive; somatostatin receptor 2; therapeutic gene; tool; trafficking; tumor

DESCRIPTION (provided by applicant): Although gene therapy and cellular therapies have great promise, they suffer from a lack of methods for specifically locating expression or cell trafficking. Reporter genes can both locate and quantify expression. In a pre-clinical tumor model, we demonstrated that transfer of a somatostatin receptor type 2a (SSTR2) gene chimera can be quantified in vivo. The growth inhibitory signaling incited by the SSTR2 may be advantageous when targeting cancer for therapy, but may not be desirable for disorders such as diabetes or when evaluating a linked gene of interest, such as for cancer. We propose to create an imagable, signaling deficient SSTR2. This reporter will have broad applicability for a number of disease states and applications. Most gene transfer techniques use constitutive promoters that drive high levels of expression in a variety of tissues. When introducing a toxic gene, promoters may be used to target tumors, and not normal tissues. Telomerase activity is found in nearly all tumors, but is absent or minimal in almost all normal tissues. This distribution is mimicked by the human telomerase reverse transcriptase (hTERT) promoter. A disadvantage of tissue specific promoters, including hTERT, is that their ability to drive transcription is relatively weak. We propose to create an amplified hTERT promoter-reporter system for tumor specific imaging. To limit effects on normal cells due to promoter leakiness or on bystander cells that can drive hTERT expression, we propose to create such constructs with signaling deficient reporters. We have quantified in vivo expression of a human somatostatin receptor gene 111 chimera in tumors using the FDA approved radiopharmaceutical in octreotide. Clinically, non-invasive methods, including anatomic imaging to assess change in tumor size, are desirable to assess efficacy. Combining functional and anatomic imaging, we will test whether the reporter system can be used to monitor expression of a linked therapeutic as well as to predict efficacy. Specific aims 1. Test the hypothesis that a signaling deficient somatostatin receptor type 2 (SSTR2) can function as a reporter of gene transfer. 2. Test the hypothesis that an amplified hTERT promoter linked to a reporter, such as a signaling deficient SSTR2 drives expression in tumors and the expression can be imaged in vivo. 3. Test the hypothesis that a signaling deficient SSTR2 linked to a therapeutic gene can be used to monitor expression and efficacy of a linked therapeutic gene. This project potentially will provide new tools for monitoring cancer treatment; as well as, increase the range of diseases that can be addressed by functional and anatomic imaging techniques, non-invasively. PUBLIC HEALTH RELEVANCE: This project potentially will provide new tools for monitoring cancer treatment; as well as, increase the range of diseases that can be addressed by functional and anatomic imaging techniques, non-invasively.

描述（由申请人提供）：虽然基因疗法和细胞疗法具有很大的前景，但它们缺乏特异性定位表达或细胞运输的方法。报告基因可以定位和量化表达。在临床前肿瘤模型中，我们证明可以在体内量化生长抑素受体 2a 型 (SSTR2) 基因嵌合体的转移。当针对癌症进行治疗时，SSTR2 引发的生长抑制信号传导可能是有利的，但对于糖尿病等疾病或评估诸如癌症等相关的相关基因时可能并不理想。我们建议创建一个可想象的、信号缺陷的 SSTR2。该报告器对于许多疾病状态和应用具有广泛的适用性。大多数基因转移技术使用组成型启动子来驱动多种组织中的高水平表达。当引入有毒基因时，启动子可用于靶向肿瘤，而不是正常组织。端粒酶活性几乎存在于所有肿瘤中，但在几乎所有正常组织中不存在或很少。这种分布是由人类端粒酶逆转录酶 (hTERT) 启动子模仿的。组织特异性启动子（包括 hTERT）的一个缺点是它们驱动转录的能力相对较弱。我们建议创建一个扩增的 hTERT 启动子-报告基因系统，用于肿瘤特异性成像。为了限制由于启动子泄漏而对正常细胞或可驱动 hTERT 表达的旁观者细胞的影响，我们建议使用信号缺陷报告基因创建此类构建体。我们使用 FDA 批准的放射性药物奥曲肽定量了肿瘤中人生长抑素受体基因 111 嵌合体的体内表达。临床上，需要非侵入性方法（包括评估肿瘤大小变化的解剖成像）来评估疗效。结合功能和解剖成像，我们将测试报告系统是否可用于监测相关治疗的表达以及预测疗效。具体目标 1. 测试信号缺陷型生长抑素受体 2 型 (SSTR2) 可以充当基因转移报告者的假设。 2. 测试以下假设：与报告基因连接的扩增 hTERT 启动子（例如信号传导缺陷的 SSTR2）驱动肿瘤中的表达，并且可以在体内对表达进行成像。 3. 测试以下假设：与治疗基因连接的信号传导缺陷的 SSTR2 可用于监测连接的治疗基因的表达和功效。该项目有可能为监测癌症治疗提供新工具；此外，还增加了可以通过功能和解剖成像技术非侵入性解决的疾病范围。公共卫生相关性：该项目有可能为监测癌症治疗提供新工具；此外，还增加了可以通过功能和解剖成像技术非侵入性解决的疾病范围。