Abstract SY42-01: Emerging epigenetic targets in high-risk pediatric solid tumors

Abstract

Abstract Pediatric cancers are typically characterized by simple genomes and key initiating events driven by aberrancy of a transcription factor or chromatin modifier. One such example is the most common extracranial solid tumor in children, neuroblastoma. Amplification of the transcription factor encoding gene MYCN is present in ∼50% of high-risk neuroblastomas, representing the best-characterized genetic marker of poor survival in these pediatric patients. We have focused on the discovery of new therapeutic strategies to targeting this recalcitrant subtype of neuroblastoma using chemical and functional genomic approaches. First, we identified BET bromodomain inhibitors as highly active in MYCN-amplified neuroblastoma in an unbiased screen of 673 diverse cancer cell lines and validated this finding using genetic suppression with shRNA and chemical inhibition with multiple BET inhibitors. Mechanistically, BET inhibitors suppress the MYCN transcriptional program and the expression of MYCN itself. Extending these studies in vivo, both to patient derived xenografts (PDX) and to genetically engineered mouse (GEM) models of MYCN-driven neuroblastoma, we demonstrated remarkable efficacy. However, this single agent approach was not curative, suggesting the need for combination therapies. In order to address this issue, we performed both gain-of-function (ORF) and loss-of-function (CRISPR/Cas9) screening of neuroblastoma cell lines treated with BET bromodomain inhibitors at an IC90 to identify potential mechanisms of resistance to treatment and to nominate targetable pathways for combination therapy. Three key pathways emerging at the intersection of these screens are under evaluation and will be presented. In parallel, we have performed a genome-wide CRISPR screen in a panel of 8 neuroblastoma cell lines, 7 of which are MYCN amplified, to identify new dependencies. In comparing neuroblastoma cell lines to over 70 non-neuroblastoma cancer cell lines, several known neuroblastoma dependencies were confirmed, including MYCN, ALK, and PHOX2B. Importantly, novel dependencies were revealed. Validated new dependencies will also be the topic of this presentation. Citation Format: Kimberly Stegmaier. Emerging epigenetic targets in high-risk pediatric solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY42-01.