A Drosophila model for Src-mediated oncogenesis

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靶点，但成功的 在带来长期治愈或缓解方面受到限制。为了实现这一难以实现的目标，进一步的工作是 需要了解癌症的复杂性，癌症是一种多基因疾病，有能力 “适应”治疗。90%的癌症死亡是由于转移造成的，这正在成为一种 癌症研究的关注度越来越高。癌症的一个根本困难是它的复杂性：它是 典型的多基因疾病，具有广泛的原位串扰。成功的药物筛查需要 来解释这些动物方面的功效。然而，到目前为止，大多数动物 复合屏幕太昂贵，无法以合理的吞吐量实现。 这项建议描述了一种利用水果进行癌症进展的整体动物方法。 会飞的果蝇。它侧重于通过激活Src而产生的单基因和多基因模型 直接或通过减少其主要负调控因子CSK的活性。提供了数据 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 刺激肿瘤外缘转化细胞的释放和转移。证据 对发生在人类鳞状细胞癌中的类似分子事件进行了研究。这 Proposal通过研究高水平的Src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，这项建议寻求建立一种新的模式 肿瘤是通过产生离散的成人‘肿瘤’而发生的。后一种模式旨在识别 引导成熟肿瘤的基因和逆转而不是预防它们的药物。 最后，这项提案建议扩大我们在候选药物发现方面的努力。我们会 通过筛选一个大型私人复合库，将我们的初始工作扩大八倍 强调“可下药的”化合物。命中率将由多个次要因素进行进一步评估 将继续进行分析和进一步研究，如初步结构/活性关系分析。 我们的目标是定义有用的化学空间，并补充我们在 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.