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Therapeutic Targeting of Ependymoma as Informed by Oncogenic Enhancer Profiling

ABSTRACT: Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts. Enhancer regions revealed novel oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, increased survival and slowed proliferation in mouse and neurosphere patient-derived models of ependymomas. This study represents one of the largest enhancer mapping study of any cancer type to date, and provides a framework for target and drug discovery for other cancers recalcitrant to therapeutic development because of their lack of known genetic drivers.

PROVIDER: EGAS00001002696 | EGA |

REPOSITORIES: EGA

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Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.

Mack Stephen C SC Pajtler Kristian W KW Chavez Lukas L Okonechnikov Konstantin K Bertrand Kelsey C KC Wang Xiuxing X Erkek Serap S Federation Alexander A Song Anne A Lee Christine C Wang Xin X McDonald Laura L Morrow James J JJ Saiakhova Alina A Sin-Chan Patrick P Wu Qiulian Q Michaelraj Kulandaimanuvel Antony KA Miller Tyler E TE Hubert Christopher G CG Ryzhova Marina M Garzia Livia L Donovan Laura L Dombrowski Stephen S Factor Daniel C DC Luu Betty B Valentim Claudia L L CLL Gimple Ryan C RC Morton Andrew A Kim Leo L Prager Briana C BC Lee John J Y JJY Wu Xiaochong X Zuccaro Jennifer J Thompson Yuan Y Holgado Borja L BL Reimand Jüri J Ke Susan Q SQ Tropper Adam A Lai Sisi S Vijayarajah Senthuran S Doan Sylvia S Mahadev Vaidehi V Miñan Ana Fernandez AF Gröbner Susanne N SN Lienhard Matthias M Zapatka Marc M Huang Zhiqin Z Aldape Kenneth D KD Carcaboso Angel M AM Houghton Peter J PJ Keir Stephen T ST Milde Till T Witt Hendrik H Li Yan Y Li Chao-Jun CJ Bian Xiu-Wu XW Jones David T W DTW Scott Ian I Singh Sheila K SK Huang Annie A Dirks Peter B PB Bouffet Eric E Bradner James E JE Ramaswamy Vijay V Jabado Nada N Rutka James T JT Northcott Paul A PA Lupien Mathieu M Lichter Peter P Korshunov Andrey A Scacheri Peter C PC Pfister Stefan M SM Kool Marcel M Taylor Michael D MD Rich Jeremy N JN

Nature 20171220 7686

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 d ...[more]

PMID: 29258295

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Project description:Background: The high incidence of recurrence and unpredictable clinical outcome for paediatric ependymoma reflect the imprecision of current therapeutic staging and need for novel risk stratification markers. Gain of chromosome 1q has been reported as a frequent aberration and correlate of adverse outcome in ependymoma. We therefore evaluated a prognostic role for 1q25 gain across three age-defined European clinical trial cohorts of paediatric intracranial ependymoma. Methods: The frequency of 1q gain in paediatric ependymoma was assessed across 51 tumours (42 primary, 9 recurrent) using Affymetrix® 500K SNP arrays. Gain of 1q25 was evaluated by interphase FISH (iFISH) across 189 primary intracranial ependymomas from children treated on the CCLG/SIOP CNS9204 (n = 60) and BBSFOP (n = 65) adjuvant chemotherapy trials, or with primary post-operative radiotherapy (SIOP CNS9904/RT group, n = 64). Results were correlated with clinical, histological and survival data. Findings: Gain of 1q was the most frequent imbalance in primary (7/42, 17 %) and recurrent ependymomas (3/9, 33 %). Gain of 1q25 was the strongest independent predictor of tumour progression in both CNS9204 (HR 3·36, p = 0·0009) and BBSFOP (HR 4·10, p = 0·0009) trial cohorts. In contrast, 1q25 gain was not prognostic for the older CNS9904/RT only group (PFS: p = 0·37, OS: p = 0·95). Clinical variables implicated in adverse outcome amongst cohorts included incomplete tumour resection and posterior fossa location. Interpretation: This is the first study to prospectively identify then validate a prognostic genomic marker for childhood ependymoma across independent prospective trial groups. 1q25 gain predicts progression in primary chemotherapy cohorts but not those treated by post-operative radiotherapy. We propose 1q25 gain is incorporated as an adverse marker into future European chemotherapeutic clinical trial design. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from flash frozen tumour specimens and patient-matched peripheral blood Copy number analysis of Affymetrix 500K SNP arrays was performed for DNA from 51 ependymomas and 40 constitutional DNA samples. Analysing broad genomic aberrations in 51 paediatric ependymomas, looking particularly at 1q gain.

Dataset Information

Therapeutic Targeting of Ependymoma as Informed by Oncogenic Enhancer Profiling

Publications

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.

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