Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Autor: Anne Song, Alexander J. Federation, Leo J.Y. Kim, David T.W. Jones, Ana Fernandez Miñan, Laura McDonald, Mathieu Lupien, Susan Q. Ke, Lukas Chavez, Briana C. Prager, Sheila K. Singh, Peter B. Dirks, Borja L. Holgado, Kristian W. Pajtler, Yan Li, Till Milde, Marc Zapatka, Angel M. Carcaboso, Livia Garzia, Xiuxing Wang, Chao Jun Li, Kenneth Aldape, Christine Lee, Ian C. Scott, Xin Wang, Laura K. Donovan, Xiu-Wu Bian, Sylvia Doan, Stephen M. Dombrowski, Betty Luu, Michael D. Taylor, Adam Tropper, Vaidehi Mahadev, James E. Bradner, Ryan C. Gimple, Tyler E. Miller, Serap Erkek, Christopher G. Hubert, Daniel C. Factor, Kulandaimanuvel Antony Michaelraj, Stefan M. Pfister, Kelsey C. Bertrand, Jennifer Zuccaro, Zhiqin Huang, Yuan Yao Thompson, Hendrik Witt, Nada Jabado, Konstantin Okonechnikov, Paul A. Northcott, James J. Morrow, Senthuran Vijayarajah, Jeremy N. Rich, Susanne Gröbner, Andrey Korshunov, Vijay Ramaswamy, Sisi Lai, Stephen C. Mack, Alina Saiakhova, Annie Huang, Claudia L.L. Valentim, James T. Rutka, Eric Bouffet, Xiaochong Wu, Matthias Lienhard, Qiulian Wu, Jüri Reimand, Peter J. Houghton, Andrew R. Morton, Peter C. Scacheri, John J.Y. Lee, Marina Ryzhova, Patrick Sin-Chan, Peter Lichter, Stephen T. Keir, Marcel Kool
Přispěvatelé: Alex's Lemonade Stand Foundation for Childhood Cancer, Cancer Prevention and Research Institute of Texas, Ministry of Science, Technology and Space (Israel), James S. McDonnell Foundation, National Institutes of Health (US)
Rok vydání: 2017
Předmět:
Zdroj: Nature
r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname
Digital.CSIC: Repositorio Institucional del CSIC
Consejo Superior de Investigaciones Científicas (CSIC)
Digital.CSIC. Repositorio Institucional del CSIC
r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
Fundació Sant Joan de Déu
ISSN: 1476-4687
0028-0836
Popis: 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 therapy1,2,3. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes1,3. 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.
This work was supported by an Alex's Lemonade Stand Young Investigator Award (S.C.M.), The CIHR Banting Fellowship (S.C.M.), The Cancer Prevention Research Institute of Texas (S.C.M., RR170023), Sibylle Assmus Award for Neurooncology (K.W.P.), the DKFZ-MOST (Ministry of Science, Technology & Space, Israel) program in cancer research (H.W.), James S. McDonnell Foundation (J.N.R.) and NIH grants: CA154130 (J.N.R.), R01 CA169117 (J.N.R.), R01 CA171652 (J.N.R.), R01 NS087913 (J.N.R.) and R01 NS089272 (J.N.R.). R.C.G. is supported by NIH grants T32GM00725 and F30CA217065. M.D.T. is supported by The Garron Family Chair in Childhood Cancer Research, and grants from the Pediatric Brain Tumour Foundation, Grand Challenge Award from CureSearch for Children’s Cancer, the National Institutes of Health (R01CA148699, R01CA159859), The Terry Fox Research Institute and Brainchild. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113).
Databáze: OpenAIRE
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