Munnik Chamoné, Xaba Malungi P, Malindisa Sibusiso T, Russell Bonnie L, Sooklal Selisha A
Department of Life and Consumer Sciences, University of South Africa, Pretoria, South Africa.
Buboo (Pty) Ltd, The Innovation Hub, Pretoria, South Africa.
Front Genet. 2022 Aug 8;13:949241. doi: 10.3389/fgene.2022.949241. eCollection 2022.
Cancer is a complex disease whereby multiple genetic aberrations, epigenetic modifications, metabolic reprogramming, and the microenvironment contribute to the development of a tumor. In the traditional anticancer drug discovery pipeline, drug candidates are usually screened using two-dimensional or three-dimensional cell culture. However, these methods fail to accurately mimic the human disease state. This has led to the poor success rate of anticancer drugs in the preclinical stages since many drugs are abandoned due to inefficacy or toxicity when transitioned to whole-organism models. The common fruit fly, , has emerged as a beneficial system for modeling human cancers. Decades of fundamental research have shown the evolutionary conservation of key genes and signaling pathways between flies and humans. Moreover, has a lower genetic redundancy in comparison to mammals. These factors, in addition to the advancement of genetic toolkits for manipulating gene expression, allow for the generation of complex genotypes and phenotypes. Numerous studies have successfully created models for colorectal, lung, thyroid, and brain cancers. These models were utilized in the high-throughput screening of FDA-approved drugs which led to the identification of several compounds capable of reducing proliferation and rescuing phenotypes. More noteworthy, has also unlocked the potential for personalized therapies. 'avatars' presenting the same mutations as a patient are used to screen multiple therapeutic agents targeting multiple pathways to find the most appropriate combination of drugs. The outcomes of these studies have translated to significant responses in patients with adenoid cystic carcinoma and metastatic colorectal cancers. Despite not being widely utilized, the concept of screening of drugs in is making significant contributions to the current drug discovery pipeline. In this review, we discuss the application of as a platform in anticancer drug discovery; with special focus on the cancer models that have been generated, drug libraries that have been screened and the status of personalized therapies. In addition, we elaborate on the biological and technical limitations of this system.
癌症是一种复杂的疾病，多种基因畸变、表观遗传修饰、代谢重编程和微环境都有助于肿瘤的发展。在传统的抗癌药物发现流程中，通常使用二维或三维细胞培养来筛选候选药物。然而，这些方法无法准确模拟人类疾病状态。这导致抗癌药物在临床前阶段的成功率很低，因为许多药物在过渡到全生物体模型时因无效或毒性而被放弃。普通果蝇已成为一种用于模拟人类癌症的有益系统。数十年的基础研究表明，果蝇和人类之间关键基因和信号通路具有进化保守性。此外，与哺乳动物相比，果蝇的基因冗余度较低。这些因素，再加上用于操纵基因表达的基因工具包的进步，使得能够产生复杂的基因型和表型。许多研究已经成功创建了结直肠癌、肺癌、甲状腺癌和脑癌的果蝇模型。这些模型被用于对FDA批准的药物进行高通量筛选，从而鉴定出几种能够减少增殖和挽救表型的化合物。更值得注意的是，果蝇还开启了个性化治疗的潜力。呈现与患者相同突变的果蝇“化身”被用于筛选针对多种途径的多种治疗药物，以找到最合适的药物组合。这些研究的结果已转化为腺样囊性癌和转移性结直肠癌患者的显著反应。尽管尚未得到广泛应用，但在果蝇中筛选药物的概念正在为当前的药物发现流程做出重大贡献。在这篇综述中，我们讨论了果蝇作为抗癌药物发现平台的应用；特别关注已生成的癌症模型、已筛选的药物库以及个性化治疗的现状。此外，我们阐述了该系统的生物学和技术局限性。
