Portal de Periódicos da CAPES

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

2017; Nature Portfolio; Volume: 553; Issue: 7686 Linguagem: Inglês

10.1038/nature25169

1476-4687

Stephen C. Mack, Kristian W. Pajtler, Lukas Chávez, Konstantin Okonechnikov, Kelsey C. Bertrand, Xiuxing Wang, Serap Erkek, Alexander Federation, Anne Song, Christine Lee, Xin Wang, Laura McDonald, James J. Morrow, Alina Saiakhova, Patrick Sin‐Chan, Qiulian Wu, Kulandaimanuvel Antony Michealraj, Tyler E. Miller, Christopher G. Hubert, Marina Ryzhova, Livia Garzia, Laura Donovan, Stephen M. Dombrowski, Daniel C. Factor, Betty Luu, Claudia L.L. Valentim, Ryan C. Gimple, Andrew R. Morton, Leo J.Y. Kim, Briana C. Prager, John J. Y. Lee, Xiaochong Wu, Jennifer Zuccaro, Yuan Thompson, Borja Holgado, Jüri Reimand, Susan Q. Ke, Adam Tropper, Sisi Lai, Senthuran Vijayarajah, Sylvia Doan, Vaidehi Mahadev, Ana Fernández‐Miñán, Susanne Gröbner, Matthias Lienhard, Marc Zapatka, Zhiqin Huang, Kenneth Aldape, Ángel M. Carcaboso, Peter J. Houghton, Stephen T. Keir, Till Milde, Hendrik Witt, Yan Li, Chaojun Li, Xiu‐Wu Bian, David Jones, Ian C. Scott, Sheila K. Singh, Annie Huang, Peter B. Dirks, Éric Bouffet, James E. Bradner, Vijay Ramaswamy, Nada Jabado, James T. Rutka, Paul A. Northcott, Mathieu Lupien, Peter Lichter, Andrey Korshunov, Peter C. Scacheri, Stefan M. Pfister, Marcel Kool, Michael D. Taylor, Jeremy N. Rich,

Neuroblastoma Research and Treatments

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. 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. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. 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). 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.