Establishing Drosophila melanogaster as part of the pre-clinical pipeline for anti-metastatic cancer drug discovery

在英国，每两分钟就有一个人被诊断出患有癌症。目前，这导致英国每年约有16.4万人死于癌症，主要是由于转移。虽然一些类型的转移性癌症可以通过现有的治疗方法治愈，但大多数无法治愈，目前的治疗方法旨在简单地阻止或减缓癌症的生长，或缓解由癌症引起的症状。这意味着迫切需要新的治疗方法。创新的体外药物筛选正在开发中，在抗转移癌症药物发现方面非常有前途。Berx和Goossens实验室已经开发了一种这样的筛查，其目标是寻找阻止称为上皮向间充质转化(EMT)的一般细胞过程的化合物。虽然EMT在正常、调节的发育过程中是必需的，但当它在癌细胞中被激活时，它可以促进细胞逃逸到体内，并促进化疗耐药。鉴于许多突变可能导致癌症转移，而且这些突变在不同个体之间可能有很大差异，我们的方法是找到阻止EMT的化合物，而不考虑上游触发因素。Berx和Goossens设计了一种复杂的高通量体外筛选，旨在寻找这样的化合物，这已经产生了一些非常令人兴奋的结果。虽然这些化合物和药物库筛选可以在培养皿中的细胞上完成，但不幸的是，癌症的扩散和转移是一个复杂的多步骤过程，只能在整个动物身上完全模拟。因此，在人类患者身上测试新化合物之前，在整个动物身上进行临床前研究对于测试它们在这方面的作用是至关重要的。因此，与许多其他研究一样，Berx/Goossens实验室在体外筛选后的下一步是在小鼠模型中测试他们识别的抗EMT化合物的有效性。由于毒性、稳定性或被人体吸收的能力等问题，许多体外鉴定的化合物在小鼠身上测试时往往失败。在这里，我们建议不要直接从体外研究转移到老鼠身上，而是引入一个步骤，首先在果蝇身上测试化合物，作为第一个端口，看看这些化合物是否在整个动物环境中起作用。我们假设，将果蝇作为体内疗效的第一个测试具有巨大的潜力，可以消除假阳性，以及在体内有毒或根本不能被人体吸收的化合物。在过去，这会受到缺乏苍蝇模型的限制，在这种模型中，细胞可以从开始迁移到在成年生物体中播种和生长，但我们最近克服了这个长期存在的限制。我们最近建立了转移性结直肠癌的果蝇模型，以及稳健、灵敏的分析方法，以量化原发肿瘤负担、循环中的肿瘤细胞和宏观继发转移的形成。我们建议将该模型引入Berx/Goossens抗EMT药物发现流水线，作为整体动物试验的第一步。虽然在临床试验之前，化合物仍需要在更接近人类的哺乳动物模型中进行测试，只需在果蝇中展示出强大的疗效，但我们实验室的初步结果表明，这将导致老鼠的使用率至少下降75%。虽然这项建议的重点是建立果蝇作为抗转移癌症药物发现的一个步骤，但我们预计，进一步模型的开发，以及展示这种果蝇-小鼠实验室合作的力量，将导致这种方法的广泛采用，并对减少药物发现过程中使用的小鼠数量产生重大影响。

Every two minutes in the UK someone is diagnosed with cancer. Currently this leads to around 164,000 cancer deaths in the UK every year, mainly from metastasis. Although some types of metastatic cancer can be cured with existing treatments, most cannot, and current treatments are aimed at simply stopping or slowing the growth of the cancer, or to relieve symptoms caused by it. This means that there is an urgent need for new therapies.Innovative new drug screens are being developed in vitro, that are very promising in terms of anti-metastatic cancer drug discovery. One such screen has been developed by the Berx and Goossens labs, which is targeted at finding compounds that block a general cell process called the epithelial-to-mesenchymal transition (EMT). While EMT is required during normal, regulated development, when activated in cancer cells it can facilitate the escape of cells into the body, as well as drive chemoresistance. Given that many mutations can contribute to cancer metastasis, and that these can differ greatly between individuals, our approach is to find compounds that block EMT regardless of the upstream triggers. Berx and Goossens have designed a sophisticated high-throughput in vitro screen aimed at finding such compounds, that has already produced a number of very exciting hits.While these compound and drug library screens can be done on cells in a dish, unfortunately cancer spreading and metastasis is a complex multi-step process that can only be fully mimicked in a whole animal. Therefore, before moving on to testing new compounds on human patients, preclinical studies in whole animals are of utmost important to test that they work in this context. The next step in the Berx/Goossens labs after in vitro screens, as in many other studies, is therefore to test the efficacy of their identified anti-EMT compounds in mouse models. Many compounds identified in vitro often fail when tested on mice, due to issues such as toxicity, stability or ability to be absorbed into the body. Here we propose to that instead of moving directly from in vitro studies - to mice, to introduce a step where compounds are first tested on Drosophila melanogaster, as a first port of call to see if the compounds will work in a whole animal context. We hypothesise that establishing Drosophila as the first test for in vivo efficacy has huge potential to eliminate false positives, along with compounds that are toxic in vivo or simply cannot be absorbed into the body. While in the past, this would have been limited by a lack of fly models where cells can be followed from initiation of migration - to seeding and growth in adult organisms, we recently overcame this longstanding limitation. We have recently generated a Drosophila model for metastatic colorectal cancer, as well as robust, sensitive assays to quantify primary tumour burden, circulating tumour cells and formation of macroscopic secondary metastases. We propose to introduce this model into the Berx/Goossens anti-EMT drug discovery pipeline, as the first step for whole animal testing. While compounds will still need to be tested in a mammalian model closer to humans before clinical trials, by only moving forward with compounds that have demonstrated robust efficacy in Drosophila, preliminary results from our labs suggest that this will lead to at least 75% drop in the use of mice. While this proposal is focused towards establishing Drosophila as a step in the pipeline for anti-metastatic cancer drug discovery, we expect that the development of further models, and demonstrating the power of such a Drosophila-mouse lab collaboration, will lead to a wide uptake of this approach, and have a great impact in reducing the numbers of mice used in the drug discovery pipeline.