Drosophila melanogaster: A platform for anticancer drug discovery and personalized therapies

Abstract

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 in vitro 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, Drosophila melanogaster, 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, Drosophila 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 Drosophila genotypes and phenotypes. Numerous studies have successfully created Drosophila 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, Drosophila has also unlocked the potential for personalized therapies. Drosophila ‘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 in vivo screening of drugs in Drosophila is making significant contributions to the current drug discovery pipeline. In this review, we discuss the application of Drosophila 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.

Synthesis, Characterization, In‐Vitro and In‐Vivo Anti‐Cancer Evaluation of Novel Benzopyrylium Salts on Colorectal Cancer Model of Drosophila Melanogaster

“…These factors, in addition to the advancement of genetic toolkits for manipulating gene expression, allow for the generation of complex Drosophila genotypes and phenotypes. [33] Scribble (scrib) is a cell polarity determinant in Drosophila and humans. Disruption in cell polarity paves the way for neoplastic cancer progression.…”

A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer

“…With its sophisticated genetic tools and practical advantages, Drosophila has a strong track record as a disease model and has also emerged as a useful drug discovery platform ( Cheng et al 2018 ; Mohr and Perrimon 2019 ; Munnik et al 2022 ). Disease models generated either by genetically manipulating Drosophila orthologs of human disease genes or directly introducing disease-associated variants of human genes into Drosophila have provided important insights into molecular mechanisms underlying human diseases, including cancer ( Verheyen 2022 ).…”

“…Disease models generated either by genetically manipulating Drosophila orthologs of human disease genes or directly introducing disease-associated variants of human genes into Drosophila have provided important insights into molecular mechanisms underlying human diseases, including cancer ( Verheyen 2022 ). Furthermore, multiple studies over the past decade have demonstrated a high degree of conservation of compound activity in Drosophila ( Su 2019 ; Munnik et al 2022 ); several compounds identified through these studies have been effective in vertebrate experimental models and human patients ( Dar et al 2012 ; Bangi et al 2016 , 2019 , 2021 ; Das et al 2018 ; Sonoshita et al 2018 ).…”

A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer

“…Drosophila, with its sophisticated genetic tools and practical advantages, has a strong track record as a disease model and has also emerged as a useful drug discovery platform (Cheng et al . 2018; Mohr and Perrimon 2019; Munnik et al . 2022).…”

“…Disease models generated either by genetically manipulating Drosophila orthologs of human disease genes or directly introducing disease associated variants of human genes into Drosophila have provided important insights into molecular mechanisms underlying human diseases including cancer (Verheyen 2022). Furthermore, multiple studies over the past decade have demonstrated a high degree of conservation of compound activity in Drosophila (Su 2019; Munnik et al . 2022); several compounds identified through these studies have been effective in vertebrate experimental models and human patients (Dar et al .…”