A Drosophila model for Src-mediated oncogenesis

描述（由申请人提供）：癌症是该国第二大常见的死亡原因，实体瘤占所有癌症的90%。它们是药物治疗的主要目标，但在长期治愈或缓解方面的成功有限。为了实现这一难以捉摸的目标，需要进一步的工作来了解癌症的复杂性，癌症是一种多基因疾病，具有“适应”治疗的能力。90%的癌症死亡是由于转移，这正在成为癌症研究的一个越来越多的焦点。癌症的一个基本困难是它的复杂性：它通常是一种具有广泛原位串扰的多基因疾病。成功的药物筛选将需要考虑这些整体动物方面的功效。然而，迄今为止，大多数完整的动物化合物筛选太昂贵而不能以合理的通量实现。该提案描述了利用果蝇的癌症进展的整体动物方法。它侧重于通过直接激活Src或通过降低其主要负调节因子Csk的活性而产生的单基因和多基因模型。提出的数据支持一种新的转移模型，其中来自邻近上皮细胞的局部信号引起转化细胞从肿瘤外边界的释放和转移。证据是类似的分子事件发生在人类鳞状细胞癌。该提案通过检查Src活性与RTK/Ras信号传导的协同作用程度来探索这些信号的性质。此外，该提案试图通过产生离散的成人“肿瘤”来建立一种新的肿瘤发生模型。后一种模型旨在识别指导成熟肿瘤的基因和逆转而不是预防它们的药物。最后，该提案建议扩大我们在候选药物发现方面的努力。我们将通过筛选一个大型私人化合物库，重点是“可药用”化合物，将我们的初步努力扩大八倍。将通过多个二级试验进一步评估命中，并将进行进一步研究，如初始结构/活性关系分析。我们的目标是定义有用的化学空间，并补充我们的遗传努力，以确定解决过度生长和转移的机制和治疗靶点。公共卫生相关性：癌症是美国第二大死亡原因，大多数死亡来自实体瘤转移。在这个提议中，我们使用果蝇作为一个整体动物模型来识别指导癌症生长和扩散的机制。此外，我们筛选化合物，定义有用的“化学空间”的治疗。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Cancer is the second leading cause of death in the United States, with most deaths deriving from solid tumor metastasis. In this proposal, we use the fruit fly Drosophila as a whole animal model to identify mechanisms that direct cancer growth and spread. In addition, we screen for compounds that define useful 'chemical space' for therapeutics.