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: 7585989
• 负责人: VIKAS KUNDRA
• 金额: $ 20.33万
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585989
• 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; Reporter; Reporter Genes; SSTR2A; Signal Transduction; Somatostatin Receptor; System; Telomerase; Testing; Therapeutic; Tissues; Toxic effect; Treatment Protocols; 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）：尽管基因疗法和细胞疗法有很大的希望，但它们缺乏专门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，我们证明了生长抑素受体2a型（SSTR2）基因嵌合体的转移可以在体内定量。 SSTR2引起的生长抑制信号传导在靶向癌症治疗时可能是有利的，但对于诸如糖尿病等疾病或评估诸如癌症之类的关联基因时，可能是不可取的。我们建议创建一个可成像的信号传导不足的SSTR2。该记者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都使用构成启动子，这些启动子在各种组织中驱动高水平的表达。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。在几乎所有肿瘤中都发现端粒酶活性，但在几乎所有正常组织中都没有或最少。人端粒酶逆转录酶（HTERT）启动子模仿这种分布。包括HTERT在内的组织特异性启动子的缺点是它们的驱动转录能力相对较弱。我们建议为肿瘤特异性成像创建一个扩增的HTERT启动子启动子系统。为了限制由于启动子泄漏或可以驱动HTERT表达的旁观者细胞引起的正常细胞的影响，我们建议用信号不足的记者创建此类构造。我们使用FDA批准的Octreotide批准的放射性药物在肿瘤中量化了人的生长抑素受体基因111嵌合体的体内表达。在临床上，需要评估功效的非侵入性方法，包括评估肿瘤大小变化的解剖成像。结合功能和解剖成像，我们将测试报告者系统是否可用于监测链接的治疗和预测功效的表达。具体目的1。检验以下假设：2型信号不足的生长抑素受体（SSTR2）可以充当基因转移的记者。 2。检验以下假设：放大的HTERT启动子与报告基因相关，例如信号不足SSTR2驱动肿瘤中的表达，并且可以在体内成像。 3。检验以下假设：与治疗基因相关的信号不足的SSTR2可用于监测连接的治疗基因的表达和功效。该项目可能会提供监测癌症治疗的新工具；同时，增加了可以通过功能和解剖成像技术来解决的疾病范围。公共卫生相关性：该项目可能会提供监测癌症治疗的新工具；同时，增加了可以通过功能和解剖成像技术来解决的疾病范围。