A Drosophila model for Src-mediated oncogenesis

描述(申请人提供)：癌症是这个国家第二大最常见的死亡来源，实体肿瘤占所有癌症的90%。它们是药物治疗的主要目标，但在带来长期治愈或缓解方面的成功一直有限。为了实现这一难以实现的目标，还需要进一步的工作来了解癌症的复杂性，癌症是一种具有“适应”治疗能力的多基因疾病。90%的癌症死亡是由于转移，这正成为癌症研究的一个日益重要的焦点。癌症的一个根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到所有动物方面的疗效。然而，到目前为止，大多数全动物复合筛都太贵了，无法达到合理的产量。这项提案描述了一种利用果蝇进行癌症进展的整体动物方法。它侧重于通过直接或通过其主要负调控因子CSK活性降低激活Src而产生的单基因和多基因模型。数据支持一种新的转移模型，在该模型中，来自邻近上皮细胞的局部信号促使转化的细胞从肿瘤的外缘释放和转移。在人类鳞状细胞癌中也出现了类似的分子事件。这项建议通过研究高的Src活性如何与RTK/RAS信号协同作用来探索这些信号的性质。此外，这项提议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肿瘤的药物。最后，这项提案建议扩大我们在候选药物发现方面的努力。我们将把最初的努力扩大八倍，通过筛选一个大型私人化合物库，重点放在“可药物”化合物上。将通过多次二次化验对HITS进行进一步评估，并将进行进一步研究，如初步结构/活性关系分析。我们的目标是定义有用的化学空间，以及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因，大多数死亡来自实体肿瘤转移。在这项建议中，我们使用果蝇作为一个完整的动物模型来确定引导癌症生长和扩散的机制。此外，我们还筛选出为治疗学定义了有用的“化学空间”的化合物。

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.