A Drosophila model for Src-mediated oncogenesis

癌症是第二个最常见的死亡原因在这个国家和实体肿瘤 占所有癌症的90%它们是药物治疗的主要目标，但成功 在长期治愈或缓解方面受到限制。为了实现这一难以捉摸的目标，进一步的工作是 需要了解癌症的复杂性，这是一种多基因疾病， “适应”治疗。90%的癌症死亡是由于转移，这正在成为一个 越来越多的癌症研究。癌症的一个根本困难是它的复杂性：它是 通常是具有广泛原位串扰的多基因疾病。成功的药物筛选需要 来解释这些动物方面的功效。然而，迄今为止， 复合筛太昂贵而不能达到合理的生产量。 该提案描述了一种利用水果的癌症进展的整体动物方法 果蝇它的重点是单基因和多基因模型通过激活Src产生 直接或通过降低其主要负调节因子Csk的活性。数据呈现 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缘释放和转移。证据 在人类鳞状细胞癌中发生的类似分子事件。这 一项提案通过研究Src的高活性如何协同作用来探索这些信号的性质 使用RTK/Ras信令。此外，该提案还寻求建立一种新的模式， 通过产生离散的成人“肿瘤”来进行肿瘤发生。后一种模式旨在确定 控制成熟肿瘤的基因和逆转而不是预防肿瘤的药物。 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，将我们最初的努力扩大八倍， 强调“可药用”化合物。点击将进一步评估多个二级 将进行分析和进一步研究，如初步结构/活性关系分析。 我们的目标是确定有用的化学空间，并补充我们的遗传努力， 确定解决过度生长和转移的机制和治疗靶点。

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.