Glioblastoma (GBM) is a heterogeneous brain tumor entity from infancy through adulthood. ALK gene fusions enriched in congenital and infant GBM have emerged as druggable driver alterations. ...Understanding the molecular basis and prevalence of ALK gene rearrangements will help define patients with GBM who may benefit from ALK-targeted therapy. See related article by Blandin et al., p. 2651.
High-grade gliomas defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active ...chromatin landscapes. We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.
Display omitted
•H3K27M mutant gliomas exhibit an enhancer landscape reflecting lineage of origin•Elevated H3K27 acetylation is pervasively distributed across the epigenome•Repeat element expression is de-repressed by H3K27M mutation•H3K27M cells are more vulnerable to DNA demethylation triggering viral mimicry
Krug et al. reveal increased global H3K27ac deposition across the genome without creation of de novo active enhancers or promoters in high-grade glioma (HGG) with H3K27M mutations. H3K27ac enrichment at repeat elements in H3K27M HGG increases their expression, conferring sensitivity to epigenetic therapies.
Accelerated discovery and collaborative research continue to highlight the remarkable progress that has been made in the diagnosis and treatment of pediatric cancers. This manuscript highlights ...important discoveries on how precision oncology is being incorporated into the diagnosis and treatment of childhood cancer at the national level to identify promising new therapies using a tumor‐agnostic approach. In addition, we have highlighted three articles that incorporate genomics and cell‐free DNA to better classify, monitor and incorporate risk‐based therapies for children with medulloblastoma. Finally, we highlighted the important role of monclonal antiobody therapy in the treatment of recurrent B‐cell leukemia and newly diagnosed high‐risk neuroblastoma.
This commentary summarizes the top advances in pediatric cancer over the past 12 months.
Ependymomas are aggressive central nervous system tumors that resist chemotherapy. In this issue of Cancer Cell, Gojo et al. dissect the single cell transcriptional landscapes of ependymoma to define ...cellular programs that mediate therapeutic resistance, tumor aggressiveness, and potential targets for therapy.
Ependymomas are aggressive central nervous system tumors that resist chemotherapy. In this issue of Cancer Cell, Gojo et al. dissect the single cell transcriptional landscapes of ependymoma to define cellular programs that mediate therapeutic resistance, tumor aggressiveness, and potential targets for therapy.
Glioblastoma is an incurable brain cancer characterized by high genetic and pathological heterogeneity. Here, we mapped active chromatin landscapes with gene expression, whole exomes, copy number ...profiles, and DNA methylomes across 44 patient-derived glioblastoma stem cells (GSCs), 50 primary tumors, and 10 neural stem cells (NSCs) to identify essential super-enhancer (SE)-associated genes and the core transcription factors that establish SEs and maintain GSC identity. GSCs segregate into two groups dominated by distinct enhancer profiles and unique developmental core transcription factor regulatory programs. Group-specific transcription factors enforce GSC identity; they exhibit higher activity in glioblastomas versus NSCs, are associated with poor clinical outcomes, and are required for glioblastoma growth in vivo. Although transcription factors are commonly considered undruggable, group-specific enhancer regulation of the MAPK/ERK pathway predicts sensitivity to MEK inhibition. These data demonstrate that transcriptional identity can be leveraged to identify novel dependencies and therapeutic approaches.
There are no effective treatment strategies for children with highest-risk posterior fossa group A ependymoma (PFA). Chromosome 1q gains (1q+) are present in approximately 25% of newly diagnosed PFA ...tumors, and this number doubles at recurrence. Seventy percent of children with chromosome 1q+ PFA will die because of the tumor, highlighting the urgent need to develop new therapeutic strategies for this population.
In this study, we utilize 1q+ PFA in vitro and in vivo models to test the efficacy of combination radiation and chemotherapy in a preclinical setting.
5-fluorouracil (5FU) enhances radiotherapy in 1q+ PFA cell lines. Specifically, 5FU increases p53 activity mediated by the extra copy of UCK2 located on chromosome 1q in 1q+ PFA. Experimental downregulation of UCK2 resulted in decreased 5FU sensitivity in 1q+ PFA cells. In in vitro studies, a combination of 5FU, retinoid tretinoin (ATRA), and radiation provided the greatest reduction in cellular proliferation and greatest increase in markers of apoptosis in 1q+ PFA cell lines compared with other treatment arms. Similarly, in vivo experiments demonstrated significant enhancement of survival in mice treated with combination radiation and 5FU and ATRA.
These results are the first to identify a chromosome 1q+ specific therapy approach in 1q+ PFA. Existing phase I studies have already established single-agent pediatric safety and dosages of 5FU and ATRA, allowing for expedited clinical application as phase II trials for children with high-risk PFA.
Abstract
Brain tumors are the leading cause of cancer-associated death in children. Ependymoma, an aggressive type of childhood brain tumor, is currently treated with surgery and radiotherapy. ...Ependymomas are a molecularly heterogeneous group of tumors driven by distinct genetic and epigenetic alterations. In children, 90% of ependymomas arise intracranially, with two thirds occurring in the posterior fossa (PF) and one third in the supratentorial brain (ST). PF ependymomas are divided into at least two groups termed, PFA and PFB, with PFA tumors associated with poor clinical outcomes. Over 70% of ST ependymoma are characterized by an oncogenic fusion between ZFTA and RELA and shown in some cohorts to have poor clinical outcome, particularly in the context of CDKN2A tumor suppressor gene loss. A major challenge in identifying therapies against ependymoma, has been the paucity of genetic abnormalities available for targeting. PFA ependymomas harbor largely balanced genomes with no recurrent CNVs, fusions, or somatic mutations that are amenable to pharmacologic inhibition. ZFTA-RELA ependymoma while representing a clear disease driver, functions as a transcription factor and lacks clear binding surfaces available for direct inhibition using small molecules. Therefore, alternative approaches are needed to identify new targets and effective therapies in ependymoma to be evaluated in pre-clinical models. In both human ependymoma cell culture lines and PDX models, we demonstrate that a multi-omic approach is promising for cell surface target discovery, and further, focused cell surface profiling can identify lead targets that can be rapidly translated for CAR T-cell therapy.
Clear cell sarcoma of the kidney (CCSK) is the second most common malignant pediatric renal tumor. Two of the recurrent somatic alterations reported in CCSK are BCL‐6 corepressor (BCOR) internal ...tandem duplication (ITD) and YWHAE‐NUTM2B/E gene fusion. A minority of patients with CCSKs have other rare somatic alterations. We report two patients with CCSK showing BCOR‐CCNB3 (where CCNB3 is cyclin B3) fusion, who had similar clinical presentation of a large renal mass with tumor thrombus extending through the inferior vena cava into the right atrium and a favorable response to chemotherapy. We recommend BCOR‐CCNB3 fusion testing for all patients with CCSK who lack BCOR‐ITD or YWHAE‐NUTM2B/E gene fusions.
PDF
