Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Abstract

SUMMARY 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. Intracranial ependymomas are segregated based on anatomical location – supratentorial region (ST) or posterior fossa (PF) – and further divided into distinct molecular subgroups that reflect differences in age of onset, gender predominance, and response to therapy1–3. 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 yet favourable clinical outcomes1,3. Greater than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NFκB subunit RELA (ST-EPN-RELA), and less frequently 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 ST and PF compartments accounting for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE, respectively1. Here, we mapped 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 were dependent. Enhancer regions revealed putative oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, diminished 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 recalcitrant to therapeutic development because of their lack of known genetic drivers.

Heterogeneity within the PF-EPN-B ependymoma subgroup

“…This is especially important in the context of the observed subtype specific copy number aberrations which suggest that PFB tumors do not emerge from a single driving event. As of today, zero recurrent mutations have been found in PFB ependymoma and a clear driver for these tumors is still lacking [10]. By focusing on specific PFB subtypes and by making use of additional molecular data like large gene expression profiling and more comprehensive next-generation-sequencing enriching for each subtype, future studies may be able to elucidate the underlying events that ultimately lead to the development of these tumors [10].…”

Childhood Cerebellar Tumors Mirror Conserved Fetal Transcriptional Programs

“…It is currently unclear to what extent the other molecular subgroups of medulloblastoma recapitulate a similar developmental hierarchy. Ependymomas are found throughout the central nervous system, but in the posterior fossa (cerebellum), are thought to be largely limited to two variants: PFA and PFB [14][15][16] , and have been suggested to arise from regional radial glial-like cells [17][18][19] . Molecular subgroups of medulloblastoma and ependymoma are delineated through transcriptomics, (gene expression) as well as patterns of DNA CpG methylation, both of which have been suggested to reflect the cell of origin for that particular molecular tumor subgroup 20,21 .…”

Case-based review: ependymomas in adults

“…Additionally, a recent study through profiling of transcriptional enhancers, also identified FGFR1 and WEE1 as possible therapeutic targets in ependymoma. 80 Owing to the rarity of these tumors, only significant collaborative efforts between clinicians and researchers will lead to further unravelling of the molecular profile and improved clinical outcomes for these patients.…”