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A Drosophila model for Src-mediated oncogenesis

Src 介导的肿瘤发生的果蝇模型

基本信息

批准号：
8469735
负责人：
Ross Leigh Cagan
金额：
$ 27.85万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8469735
关键词：
Accounting Address Adult Affect Animal Model Animals Antineoplastic Agents Biological Assay Biology Breast Cancer Cell Cancer Biology Cancer Model Cause of Death Cell Culture Techniques Cessation of life Chemicals Complement Country Data Disease Disease remission Drosophila genus Drug Targeting Epidermal Growth Factor Receptor Epithelial Cells Event Genes Genetic Goals Growth Human In Situ Laboratories Libraries Malignant Neoplasms Maps Mediating Metastatic Neoplasm to the Lung Modeling Molecular Mus Mutation Nature Neoplasm Metastasis Orthologous Gene Pathway interactions Pharmaceutical Preparations Phenotype Preclinical Drug Evaluation Signal Transduction Solid Neoplasm Source Squamous cell carcinoma Structure-Activity Relationship Therapeutic Tumor Suppressor Genes United States Work anticancer research cell transformation combinatorial design drug discovery fly improved mortality novel novel therapeutics prevent screening success therapeutic target tool tumor tumor progression tumorigenesis

项目摘要

Cancer is the second most common source of mortality in this country and solid tumors account for 90% of all cancers. They are a primary target for drug therapeutics but success has been limited in bringing long-term cure or remission. To achieve this elusive goal, further work is needed to understand the complexity of cancer, which is a multigenic disease with the ability to 'adapt' to treatment. 90% of cancer deaths are due to metastasis and this is becoming an increasing focus of cancer research. A fundamental difficulty of cancer is its complexity: it is typically a multigenic disease with extensive in situ crosstalk. Successful drug screens will need to account for these whole animal aspects of efficacy. To date, however, most whole animal compound screens are too expensive to achieve at a reasonable throughput. This proposal describes a whole animal approach to cancer progression utilizing the fruit fly Drosophila. It focuses on single and multigenic models generated through activation of Src either directly or through reduced activity of its major negative regulator Csk. Data is presented supporting a novel model of metastasis in which local signals from neighboring epithelial cells provoke release and metastasis of transformed cells from the outer border of tumors. Evidence is presented for similar molecular events occurring in human squamous cell carcinomas. This proposal explores the nature of these signals by examining how high Src activity acts in synergy with RTK/Ras signaling. In addition, this Proposal seeks to establish a novel model of tumorigenesis by generating discrete adult 'tumors'. This latter model is designed to identify genes that direct mature tumors and drugs that reverse rather than prevent them. Finally, this proposal proposes to expand our efforts in candidate drug discovery. We will expand our initial efforts eight-fold by screening a large private compound library with an emphasis on 'druggable' compounds. Hits will be further assessed by multiple secondary assays and further studies such as initial structure/activity relationship analysis will be pursued. The goal is to define useful chemical space as well as complement our genetic efforts towards identifying mechanisms and therapeutic targets that address overgrowth and metastasis.

癌症是这个国家第二大最常见的死亡原因，其次是实体瘤