Abstract 2666: Subtype-selective lethal molecules disrupt the regulatory module that drives high-risk neuroblastoma

Abstract

Abstract Neuroblastoma (NBL) is a tumor that is derived from the developing neural crest, resulting in approximately 15% of pediatric cancer deaths. This cancer is characterized by multiple tumor subtypes that vary in their aggressiveness and clinical prognosis. Though MYCN amplification is associated with an aggressive subtype and poor prognosis, recent molecular classification identified a novel aggressive subtype driven by a mesenchymal gene signature. To understand the molecular mechanisms underpinning each subtype, network-based analysis identified key transcriptional regulators for each subtype that act in concert to drive tumor pathology. We hypothesize that chemical inhibitors disrupting this regulatory module will have greater chance of success in vivo, by targeting the specific drivers of the tumor subtype. In an effort to identify subtype-selective lethal molecules that could be developed into targeted therapies, we screened ~5500 bioactive molecules across a panel of four NBL cell lines representing either MycNAMP or the newly identified mesenchymal subtype (MESN). A number of subtype selective compounds were identified, and their effect on the regulatory module was evaluated using high-throughput transcriptome analysis (PLATE-Seq) (Bush EC et al., 2017) followed by Virtual Inference of Protein activity by Enriched Regulon (VIPER) analysis (Alvarez MJ et al., 2016). This analysis revealed 15 compounds that exhibited greater potency in MycNAMP cells, and inverted the MR signature that characterizes this subtype. Compounds that reverted the signature caused destabilization of MycN through diverse mechanisms, highlighting new therapeutic approaches to targeting the MycNAMP subtype. This screening strategy also identified MESN-selective compounds, including multiple statin drugs that inhibit mevalonate biosynthesis in cells. The subtype-selectivity of these well-studied drugs is being used to define their lethal mechanisms in the MESN subtype, and to understand how MycNAMP cells evade their inhibitory effects. Our multifaceted approach, including cell line-selective chemical screening coupled with high-throughput transcriptome and network analysis, can serve as a framework for future drug discovery in a variety of cancers. Citation Format: Michael E. Stokes, Alessandro Vasciaveo, Jonnell Candice Small, Presha Rajbhandari, Gonzalo Lopez, Andrea Califano, Brent R. Stockwell. Subtype-selective lethal molecules disrupt the regulatory module that drives high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2666.