Developing Multi-Genic Anti-Breast Cancer Therapies

开发多基因抗乳腺癌疗法

• 批准号: 7036407
• 负责人: ROBERT J DEBS
• 金额: $ 29.23万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-10 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036407
• 关键词: angiogenesis; athymic mouse; breast neoplasms; carcinoma; complementary DNA; gene expression; gene expression profiling; gene interaction; gene therapy; host neoplasm interaction; laboratory mouse; metastasis; microarray technology; neoplasm /cancer genetics; neoplasm /cancer therapy; transfection /expression vector; tumor suppressor genes

DESCRIPTION (provided by applicant): The metastatic progression of breast cancer is caused by the aberrant-expression of multiple different genes. We will test the overall hypothesis that breast cancer can be treated more effectively by coordinately correcting linked-genetic errors required for its metastatic progression. We have shown that FKBP/38 and Id- 1 gene sets play significant roles in metastatic progression. Our multi-cassette vectors can efficiently express multiple different genes in tumor-bearing mice. We propose to use systemic transfer of FKBPr38- and ld-1- linked genes to more effectively block the metastatic progression of murine (4T1) and of human (MDA-MB- 231) breast carcinomas in mice. To achieve these goals we will conduct experiments summarized in our three specific aims. Aim 1. To assess the effects of systemic expression of the FKBPK38, or ld-2 genes, and of systemic, targeting of the ld-1, MMP-9 or MT1-MMP genes on the metastatic progression of breast carcinomas in mice. Aim 1 will measure the anti-metastatic activities of each of these genes or anti-genes when administered individually in mice bearing mice well-established metastases, as well as assess target gene modulation at three different time points. Aim 2: To identify combinations of FKBPK38- or ld-1-linked genes that maximally suppress the metastatic progression of breast cancers in tumor-bearing mice. This aim will measure metastatic progression in conjunction with tumor angiogenesis, proliferation and/or apoptosis in order to test the following hypotheses: Metastatic breast cancers, since they are caused by multi-genie abnormalities, will be more effectively be treated by combinations of linked anti-tumor genes. Aim 3: To determine whether effective anti-tumor gene(s) and/or anti-gene(s) act primarily within tumor cells, or act within the tumor microenvironment as well. This aim will test the hypothesis that some effective anti- metastatic genes or anti-genes act primarily within tumor cells, whereas, others produce their effects, at least in part, by altering gene expression within the tumor microenvironment. In summary, we will attempt to identify combinations of linked anti-tumor genes and anti-genes that can more effectively block the metastatic progression of breast cancers than mono-genic interventions. The most effective combinations can be specifically targeted by emerging small molecule-, protein- and gene-based therapeutic approaches.

描述（由申请人提供）：乳腺癌的转移性进展是由多个不同基因的异常表达引起的。我们将通过协调纠正其转移性进展所需的连接的遗传误差来检验的总体假设，即乳腺癌可以更有效地治疗。我们已经表明，FKBP/38和ID-1基因集在转移性进程中起着重要作用。我们的多组载体可以有效地表达含有肿瘤的小鼠的多个不同基因。我们建议使用FKBPR38-和LD-1链接基因的全身转移，以更有效地阻止小鼠中鼠（4T1）和人（MDA-MB-231）乳腺癌的转移进展。为了实现这些目标，我们将在我们的三个特定目标中进行总结的实验。目的1。评估FKBPK38或LD-2基因的全身表达的影响，以及全身性，靶向LD-1，MMP-9或MT1-MMP基因对小鼠乳腺癌的转移性进展。 AIM 1将在带有良好成熟的转移的小鼠中单独施用的小鼠中分别施用这些基因或抗生物的抗转移活性，并在三个不同的时间点评估靶基因调节。目标2：确定FKBPK38或LD-1连接基因的组合，从而最大程度地抑制了肿瘤小鼠乳腺癌的转移进展。该目标将与肿瘤血管生成，增殖和/或凋亡结合使用以检验以下假设来衡量转移性进展：转移性乳腺癌，因为它们是由多生成异常引起的，将受到多生成的异常的影响。目标3：确定有效的抗肿瘤基因和/或抗基因是主要在肿瘤细胞内作用，还是在肿瘤微环境内作用。该目的将检验以下假设：某些有效的抗转移基因或抗生物主要起作用在肿瘤细胞内，而另一些抗生物的作用至少部分通过改变肿瘤微环境中的基因表达而产生其作用。总而言之，我们将尝试确定与单基因干预措施相比，可以更有效地阻止乳腺癌的转移进展的连接的抗肿瘤基因和抗生物的组合。最有效的组合可以通过出现的小分子，蛋白质和基因的治疗方法来特异性。