A CRISPRi Genetic Screen in Ewing sarcoma Identifies a Novel Dependence on Homologous Recombination DNA Repair
Sarcomas are tumors of the bone and soft tissues that comprise up to 20% of cancer diagnoses in children. Despite dismal outcomes for patients with recurrent or metastatic disease, treatment regimens consisting of intense non-specific chemotherapy combined with surgery or radiation remain largely unchanged for decades.
My proposal focuses on Ewing's sarcoma (ES), a bone tumor characterized by a unique genetic change that creates a tumor-specific protein EWS-FLI1. To date, no drug has been identified to directly block the cancer causing EWS-FLI1 protein. My proposal suggests an alternative approach: can we identify a targetable weakness in ES that is caused by the EWS-FLI1 protein? To date, I have used a cutting-edge screening technology called CRISPR interference to test 7,000 genes and identify those that specifically kill ES cells.
My preliminary results identify a previously unknown vulnerability of ES cells: a dependence on a specific type of DNA repair process called homologous recombination (HR). While many redundant strategies exist in normal cells to repair DNA damage, I propose that EWS-FLI1 causes ES cells to become overly reliant on the HR pathway, such that blocking HR is an effective and specific way to target ES. My proposal aims to understand how the unique ES protein EWS-FLI1 creates this dependency on HR repair and more generally how it interacts with the machinery that responds to DNA damage. This work has the potential to identify a new targetable pathway in ES and could lead to novel, less toxic, more effective treatments for patients.
"Alex's Lemonade Stand Foundation's Young Investigator Grant provides invaluable research funding and support to allow me to continue studying a new genetic dependence in Ewing's sarcoma, a pediatric bone cancer. The goal of my research is to understand how DNA repair mechanisms are disrupted in Ewing's sarcoma and translate that knowledge into new and improved therapeutic strategies. This work would be impossible without the support of Alex's Lemonade Stand Foundation." - Asmin Tulpule, MD/PhD