Identifying Novel Cancer Therapies Using Chemical Genetics and Zebrafish

Abstract

Chemical genetics is the use of small molecules to perturb biological pathways. This technique is a powerful tool for implicating genes and pathways in developmental programs and disease, and simultaneously provides a platform for the discovery of novel therapeutics. The zebrafish is an advantageous model for in vivo high-throughput small molecule screening due to translational appeal, high fecundity, and a unique set of developmental characteristics that support genetic manipulation, chemical treatment, and phenotype detection. Chemical genetic screens in zebrafish can identify hit compounds that target oncogenic processes– including cancer initiation and maintenance, metastasis, and angiogenesis–and may serve as cancer therapies. Notably, by combining drug discovery and animal testing, in vivo screening of small molecules in zebrafish has enabled rapid translation of hit anti-cancer compounds to the clinic, especially through the repurposing of FDA-approved drugs. Future technological advancements in automation and high-powered imaging, as well as the development and characterization of new mutant and transgenic lines, will expand the scope of chemical genetics in zebrafish.

Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment

“…Strategies for drug repurposing include a chemogenomic library in phenotypic screen, 22 in silico computational drug repositioning, 23 pairwise combinatorial screen of drugs against molecular targets of interest 24 and novel in vivo model systems such as zebrafish. 25 The use of cytotoxic docetaxel chemotherapy is well established in metastatic prostate cancer, but only results in a modest survival benefit. Cabazitaxel is approved by the FDA as a second-line chemotherapy treatment; however, again the survival benefit is only moderate, leaving an unmet need for improved therapies.…”

Zebrafish: Speeding Up the Cancer Drug Discovery Process

“…Direct administration requires invasive intraperitoneal or retro-orbital injection, which could prevent long-term drug assays (79,80). To overcome this drawback, Dang and colleagues developed an oral gavage and anesthesia method in adult zebrafish for cancer preclinical studies (81). Furthermore, artificial oil bodies with phospholipids have been developed in order to obtain noninvasive drug administration (82).…”

Drug repurposing for Dravet syndrome in scn1Lab−/− mutant zebrafish

“…Zebrafish‐based models are also amenable to fast screening of large libraries in a target‐unbiased phenotypic way. As a consequence, they are well fitted to function as discovery platforms for drug repurposing testing, for example, in the search for new therapeutic candidates to treat DS patients and possibly other drug‐resistant epilepsies …”

“…4,5 Zebrafish-based models are also amenable to fast screening of large libraries in a target-unbiased phenotypic way. As a consequence, they are well fitted to function as discovery platforms for drug repurposing testing, 6 for example, in the search for new therapeutic candidates to treat DS patients and possibly other drug-resistant epilepsies. 5 Using the zebrafish scn1Lab −/− mutant model of DS, recently the role of serotonergic (5-HT) modulation in treating drug-resistant seizures was underlined.…”