Developing Multi-Genic Anti-Breast Cancer Therapies

开发多基因抗乳腺癌疗法

基本信息

批准号：
7362399
负责人：
ROBERT J DEBS
金额：
$ 28.39万
依托单位：
CALIFORNIA PACIFIC MED CTR RES INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-10 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7362399
关键词：
Adhesions Affect Apoptosis Breast Breast Cancer Cell Breast Carcinoma Cancer Etiology Cancer Patient Cell Adhesion Cell Cycle Regulation Cell physiology Clinical Complex Development Disease Distal Dose Down-Regulation End Point Etiology Gelatinase B Gene Combinations Gene Expression Gene Expression Profile Gene Expression Profiling Gene Proteins Gene Targeting Gene Transfer Genes Genetic Genie Goals Human Individual Intervention Invasive Lead Life Link Liposomes MMP14 gene Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mammary gland Matrix Metalloproteinases Measures Mediating Mediator of activation protein Molecular Mono-S Mus Mutation Neoplasm Metastasis Nude Mice Numbers Pathogenesis Pathway interactions Patients Plasmid Cloning Vector Plasmids Play Principal Investigator Rate Research Personnel Role Solid Neoplasm Tacrolimus Binding Protein 1A Testing Therapeutic Time Transcriptional Activation Transfection Treatment Protocols Triplet Multiple Birth Tumor Angiogenesis Tumor Cell Invasion Up-Regulation Xenograft procedure angiogenesis base cDNA Arrays cancer therapy design human MMP14 protein malignant breast neoplasm neoplastic cell novel outcome forecast programs research study small molecule syndecan tumor vector

项目摘要

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-genie interventions. The most effective combinations can be specifically targeted by emerging small molecule-, protein- and gene-based therapeutic approaches.

乳腺癌的转移进展是由多种不同的异常表达引起的基因。我们将测试总体假设，即可以通过协调可以更有效地治疗乳腺癌纠正其转移进展所需的链接的遗传错误。我们已经证明了FKBP/38和ID- 1个基因集在转移性进展中起着重要作用。我们的多组矢量可以有效地表达肿瘤小鼠中多个不同的基因。我们建议使用FKBPR38-和LD-1-的系统转移连接的基因以更有效地阻止鼠（4T1）和人的转移进展（MDA-MB- 231）小鼠的乳腺癌。为了实现这些目标，我们将进行总结的实验三个具体目标。目的1。评估FKBPK38或LD-2基因的全身表达的影响全身性，靶向LD-1，MMP-9或MT1-MMP基因在乳腺转移性进展上小鼠的癌。 AIM 1将测量这些基因或抗创建的每个基因的抗转移活性当在带有完善的转移的小鼠的小鼠中分别施用时，并评估靶标基因调制在三个不同的时间点。目标2：确定FKBPK38-或LD-1连接的组合最大程度抑制肿瘤小鼠乳腺癌转移性进展的基因。这个目标将在肿瘤血管生成，增殖和/或凋亡中测量转移性进展为了检验以下假设：转移性乳腺癌，因为它们是由多生物引起的异常，将通过连接的抗肿瘤基因的组合来更有效地治疗。目标3：到确定有效的抗肿瘤基因和/或抗基因是主要作用于肿瘤细胞内还是作用在肿瘤微环境中。这个目标将检验以下假设，即某些有效的抗转移基因或抗生物主要作用于肿瘤细胞中，而其他基因至少产生其作用，至少在某种程度上，通过改变肿瘤微环境中的基因表达。总而言之，我们将尝试确定可以更有效地阻止的抗肿瘤基因和抗生物的组合乳腺癌的转移性进展比单生物干预措施。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地针对。