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）：尽管基因治疗和细胞治疗具有很大的前景，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定量表达。在临床前肿瘤模型中，我们证明了生长抑素受体2a型（SSTR 2）基因嵌合体的转移可以在体内定量。当靶向癌症用于治疗时，由SSTR 2激发的生长抑制信号传导可能是有利的，但对于诸如糖尿病的病症或当评估诸如癌症的相关基因时可能不是期望的。我们建议创建一个可成像的，信号缺陷的SSTR 2。该报告器将对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，其驱动在多种组织中的高水平表达。当引入毒性基因时，启动子可用于靶向肿瘤，而不是正常组织。端粒酶活性几乎在所有肿瘤中发现，但几乎在所有正常组织中不存在或极低。这种分布由人端粒酶逆转录酶（hTERT）启动子模拟。组织特异性启动子（包括hTERT）的缺点是它们驱动转录的能力相对较弱。我们建议建立一个扩增的hTERT启动子-报告系统，用于肿瘤特异性成像。为了限制由于启动子泄漏对正常细胞的影响或对可以驱动hTERT表达的旁观者细胞的影响，我们建议用信号传导缺陷型报告基因创建这样的构建体。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。在临床上，非侵入性方法，包括解剖成像，以评估肿瘤大小的变化，是可取的，以评估疗效。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（SSTR 2）可以作为基因转移的报告基因的假设。2.检验扩增的hTERT启动子与报告基因（如信号传导缺陷型SSTR 2）连接驱动肿瘤中的表达，并且表达可以在体内成像的假设。3.检验与治疗性基因连接的信号传导缺陷型SSTR 2可用于监测连接的治疗性基因的表达和功效的假设。该项目可能会为监测癌症治疗提供新的工具;以及，增加可以通过功能和解剖成像技术非侵入性地解决的疾病范围。公共卫生关系：该项目可能会为监测癌症治疗提供新的工具;以及，增加可以通过功能和解剖成像技术非侵入性地解决的疾病范围。