Abstract IA25: Modeling cancer in the CRISPR era

Abstract

Abstract Chromosomal rearrangements are common cancer-associated mutations that often result in the generation of therapeutically actionable gene fusions. Unfortunately, until recently this class of mutations has proved challenging to recapitulate using conventional gene-targeting methods. To overcome this limitation, we have recently developed a CRISPR-based strategy to model a broad range of chromosomal rearrangements, including inversions, deletions, translocations, and tandem duplications (Maddalo et al., 2014). Since this strategy can be used to induce the desired chromosomal rearrangement in somatic cells—ex vivo or directly in vivo—of adult animals, it enables the rapid and cost-effective generation of novel mouse models of human cancer. As proof of concept, we have applied this strategy to generate a novel model of EML4-ALK driven lung adenocarcinoma, and to show that a novel gene fusion observed in a few human gliomas is a potent oncogenic driver and therapeutic target (Cook et al., 2017; Maddalo et al., 2014; Ventura, Dow, 2018). In my presentation, I will discuss how my group is using these novel technologies, as well as conventional gene-targeting methods, to recapitulate the genetic complexity of human cancers in vivo. I will present new and unpublished models of pediatric brain cancers driven by BRAF gene fusions we have recently generated using in vivo and ex vivo CRISPR-mediated chromosomal engineering and show how we are using these models to test novel therapeutic strategies and to gain insights into the molecular pathogenesis of human cancers.