Journal Article

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Dirks, Peter B., Wang, Xin, Prager, Briana C., Bouffet, Eric, Northcott, Paul A., Keir, Stephen T., Korshunov, Andrey, Ramaswamy, Vijay, Lee, John J. Y., Saiakhova, Alina, Scacheri, Peter C., Rutka, James T., Okonechnikov, Konstantin, Ryzhova, Marina, Lai, Sisi, Bradner, James E., Pfister, Stefan M., Dombrowski, Stephen, Thompson, Yuan, Milde, Till, Singh, Sheila K., Lupien, Mathieu, Luu, Betty, Garzia, Livia, Wu, Qiulian, Miñan, Ana Fernandez, Donovan, Laura, Zapatka, Marc, Federation, Alexander, Aldape, Kenneth D., Bertrand, Kelsey C., Taylor, Michael D., Sin-Chan, Patrick, Huang, Annie, Doan, Sylvia, Li, Chao-Jun, Wang, Xiuxing, Lee, Christine, Morton, Andrew, Pajtler, Kristian W., Morrow, James J., Carcaboso, Angel M., Chavez, Lukas, Tropper, Adam, Vijayarajah, Senthuran, Scott, Ian, Houghton, Peter J., Michaelraj, Kulandaimanuvel Antony, Kim, Leo, Li, Yan, Bian, Xiu-Wu, Valentim, Claudia L. L., Ke, Susan Q., Factor, Daniel C., Huang, Zhiqin, Rich, Jeremy N., Erkek, Serap, McDonald, Laura, Reimand, Jüri, Jones, David T. W., Miller, Tyler E., Zuccaro, Jennifer, Lienhard, Matthias, Mack, Stephen C., Hubert, C

2018

Overview

Super enhancers regulate oncogenes and other molecular targets in ependymomas, and identification of these genes provides potential therapeutic targets. Targeting brain tumours Ependymomas are chemotherapy-resistant brain tumours, which lack effective molecular targets for the development of therapeutics. Here, Jeremy Rich and colleagues map transcriptionally active regulatory regions in primary ependymomas to identify super-enhancer-associated genes and define distinct enhancer landscapes between molecular subgroups of ependymoma. They find putative oncogenes and other molecular targets that are regulated by these enhancers and confirm the importance of these genes for cancer cell growth by using RNAi knockdown or small-molecule inhibitor approaches. The study exemplifies how information about enhancer landscapes can be applied to dissect molecular differences between tumours and help guide future development of precision therapies. Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy 1 , 2 , 3 . The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations 2 . Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes 1 , 3 . More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1) 1 , 3 , 4 . Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/89 / 38/39 / 38/47 / 45/15 / 45/91 / 49/23 / 631/67/68/2486 / 631/67/69 / 692/699/67/1922 / Animal models / Animals / Base Sequence / Brain / Brain cancer / Brain tumors / Cancer genetics / Cancer research / Cancer therapies / Care and treatment / Chemotherapy / Chromatin / Deoxyribonucleic acid / DNA / DNA methylation / Drug discovery / Enhancer Elements, Genetic - genetics / Enhancers / Ependymoma - classification / Ependymoma - drug therapy / Ependymoma - genetics / Ependymoma - pathology / Female / Gene expression / Gene Expression Regulation, Neoplastic / Gene fusion / Gene mapping / Gene Regulatory Networks - genetics / Gene sequencing / Genetic aspects / Genomics / Gliomas / Humanities and Social Sciences / Humans / letter / Medical research / Mice / Molecular Targeted Therapy / multidisciplinary / Neurospheres / NF-κB protein / Oncogenes - genetics / Physiological aspects / Precision Medicine / RelA protein / Ribonucleic acid / RNA / RNA Interference / Science / Therapeutic targets / Transcription / Transcription Factors - metabolism / Tumors / Xenograft Model Antitumor Assays / Yes-associated protein