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Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.

Publication ,  Journal Article
Mack, SC; Pajtler, KW; Chavez, L; Okonechnikov, K; Bertrand, KC; Wang, X; Erkek, S; Federation, A; Song, A; Lee, C; Wang, X; McDonald, L ...
Published in: Nature
January 4, 2018

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.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

January 4, 2018

Volume

553

Issue

7686

Start / End Page

101 / 105

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Transcription Factors
  • RNA Interference
  • Precision Medicine
  • Oncogenes
  • Molecular Targeted Therapy
  • Mice
  • Humans
  • General Science & Technology
  • Gene Regulatory Networks
 

Citation

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Mack, S. C., Pajtler, K. W., Chavez, L., Okonechnikov, K., Bertrand, K. C., Wang, X., … Rich, J. N. (2018). Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature, 553(7686), 101–105. https://doi.org/10.1038/nature25169
Mack, Stephen C., Kristian W. Pajtler, Lukas Chavez, Konstantin Okonechnikov, Kelsey C. Bertrand, Xiuxing Wang, Serap Erkek, et al. “Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.Nature 553, no. 7686 (January 4, 2018): 101–5. https://doi.org/10.1038/nature25169.
Mack SC, Pajtler KW, Chavez L, Okonechnikov K, Bertrand KC, Wang X, et al. Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature. 2018 Jan 4;553(7686):101–5.
Mack, Stephen C., et al. “Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.Nature, vol. 553, no. 7686, Jan. 2018, pp. 101–05. Pubmed, doi:10.1038/nature25169.
Mack SC, Pajtler KW, Chavez L, Okonechnikov K, Bertrand KC, Wang X, Erkek S, Federation A, Song A, Lee C, McDonald L, Morrow JJ, Saiakhova A, Sin-Chan P, Wu Q, Michaelraj KA, Miller TE, Hubert CG, Ryzhova M, Garzia L, Donovan L, Dombrowski S, Factor DC, Luu B, Valentim CLL, Gimple RC, Morton A, Kim L, Prager BC, Lee JJY, Wu X, Zuccaro J, Thompson Y, Holgado BL, Reimand J, Ke SQ, Tropper A, Lai S, Vijayarajah S, Doan S, Mahadev V, Miñan AF, Gröbner SN, Lienhard M, Zapatka M, Huang Z, Aldape KD, Carcaboso AM, Houghton PJ, Keir ST, Milde T, Witt H, Li Y, Li C-J, Bian X-W, Jones DTW, Scott I, Singh SK, Huang A, Dirks PB, Bouffet E, Bradner JE, Ramaswamy V, Jabado N, Rutka JT, Northcott PA, Lupien M, Lichter P, Korshunov A, Scacheri PC, Pfister SM, Kool M, Taylor MD, Rich JN. Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature. 2018 Jan 4;553(7686):101–105.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

January 4, 2018

Volume

553

Issue

7686

Start / End Page

101 / 105

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Transcription Factors
  • RNA Interference
  • Precision Medicine
  • Oncogenes
  • Molecular Targeted Therapy
  • Mice
  • Humans
  • General Science & Technology
  • Gene Regulatory Networks