Abstract 1106: Genome-wide CRISPR-Cas9 screens reveal candidate therapeutic targets and tumor suppressor genes for human glioma

Glioblastoma multiforme (GBM) is the most aggressive and common form of brain cancer in adults. There are currently no effective therapies for GBM. Even with standard of care treatments, such as surgery, radiation, and chemotherapy, ∼90% of adult patients die within 2 years of diagnosis. Our inability to develop new more effective therapies may arise from pre-clinical models that inadequately predict therapeutic window and the fact that many new GBM drugs are “hand-me-downs” from other cancers, not specifically developed for treating brain tumors. To identify patient-tailored drug targets for GBM, our group has performed a series of functional genetic screens in patient derived GBM stem-like cells (GSCs) and also non-transformed human neural stem cells (NSCs). GSCs retain tumor-initiating potential and tumor-specific genetic and epigenetic signatures, even during extended outgrowth in serum-free culture. NSCs represent non-transformed candidate cell of origin controls, which share similar gene expression signatures and identical in vitro growth conditions. Using these systems along with RNAi or CRISPR/Cas9 platforms, we have identified multiple molecular vulnerabilities specific to GSCs, which appear to be largely driven by oncogenic transformation, in processes ranging from kinetochore regulation to 3′ pre-mRNA splice site recognition. At this meeting, we present our latest findings from genome-wide CRISPR-Cas9 gene knockout screens in multiple GSC and NSC isolates. These include validation studies of patient tumor-lethal genes using gene knockout rather than gene knockdown technology. In addition, we will present validation studies of gene products growth limiting for NSC expansion/self-renewal from these screens, a subset of which are candidate tumor suppressors for glioma. Strengths and weaknesses of using gene editing technology and GSC isolates for identification of therapeutic targets will be discussed. Citation Format: Yu Ding, Chad Toledo, Pia Hoellerbauer, Ryan Basom, Emily Girad, Eunjee Lee, Philip Corrin, Qi Lin, Xiao-Nan Li, Do-Hyun Nam, Jeongwu Lee, Jun Zhu, Steven Pollard, Jeffery Delrow, Jim Olson, Patrick J. Paddison. Genome-wide CRISPR-Cas9 screens reveal candidate therapeutic targets and tumor suppressor genes for human glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1106. doi:10.1158/1538-7445.AM2015-1106