Abstract PR07: Synthetic lethal screens in zebrafish

Abstract

Abstract The zebrafish embryo enables high-content screens in the intact, whole vertebrate. The system is particularly amenable to drug screening (up to 96-well format), and the mechanism of action of identified compounds can be readily dissected via morpholino or mRNA microinjections in live embryos (Sidi et al., Cell 133:864-77, 2008). We are exploiting zebrafish lines bearing cancer-relevant mutations (e.g., p53, pten, brca2 mutants) as platforms for synthetic lethal screens, focusing mainly on libraries of kinase inhibitors or FDA-approved compounds. Drugs that selectively induce cell lethality in mutant but not wild-type embryos are rescreened against panels of genetically annotated human cancer cell lines. A key advantage of the whole-embryo approach is the ability to identify those cell- or tissue-types in which the synthetic interaction occurs, thus guiding our human cancer cell-based validation screens. We will discuss the results of our large-scale screens targeted to p53, performed in the presence or absence of ionizing radiation-induced DNA damage. This abstract is also presented as Poster A11. Citation Format: Samuel Sidi. Synthetic lethal screens in zebrafish. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR07.