CAR T cell therapy for pediatric central nervous system tumors: a review of the literature and current North American trials.

Central nervous system (CNS) tumors are the leading cause of cancer-related death in children. Typical therapy for CNS tumors in children involves a combination of surgery, radiation, and chemotherapy. While upfront therapy is effective for many high-grade tumors, therapy at the time of relapse remains limited.

Concurrent ependymal and ganglionic differentiation in a subset of supratentorial neuroepithelial tumors with EWSR1-PLAGL1 rearrangement.

Neuroepithelial tumors with fusion of PLAGL1 or amplification of PLAGL1/PLAGL2 have recently been described often with ependymoma-like or embryonal histology respectively. To further evaluate emerging entities with PLAG-family genetic alterations, the histologic, molecular, clinical, and imaging features are described for 8 clinical cases encountered at St. Jude (EWSR1-PLAGL1 fusion n = 6; PLAGL1 amplification n = 1; PLAGL2 amplification n = 1).

Dominant Malignant Clones Leverage Lineage Restricted Epigenomic Programs to Drive Ependymoma Development.

Unlabelled: ZFTA-RELA is the most recurrent genetic alteration seen in pediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumors in mice. Despite ZFTA-RELA's potent oncogenic potential, gene fusions are observed exclusively in childhood EPN, with tumors located distinctly in the supratentorial region of the central nervous system (CNS). We hypothesized that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZFTA-RELA.

Histone serotonylation regulates ependymoma tumorigenesis.

Bidirectional communication between tumours and neurons has emerged as a key facet of the tumour microenvironment that drives malignancy. Another hallmark feature of cancer is epigenomic dysregulation, in which alterations in gene expression influence cell states and interactions with the tumour microenvironment. Ependymoma (EPN) is a paediatric brain tumour that relies on epigenomic remodelling to engender malignancy; however, how these epigenetic mechanisms intersect with extrinsic neuronal signalling during EPN tumour progression is unknown.

Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma.

Purpose: 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.

A Molecular Blueprint to Targeting ALK Gene Fusions in Glioblastoma.

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.

Significant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: A multicenter study.

Background: Ependymoma (EPN) posterior fossa group A (PFA) has the highest rate of recurrence and the worst prognosis of all EPN molecular groups. At relapse, it is typically incurable even with re-resection and re-irradiation. The biology of recurrent PFA remains largely unknown; however, the increasing use of surgery at first recurrence has now provided access to clinical samples to facilitate a better understanding of this.

Recent Advancements in Ependymoma: Challenges and Therapeutic Opportunities.

Background: Ependymoma is one of the most common malignant pediatric brain tumors and can be difficult to treat. Over the last decade, much progress has been made in the understanding of the underlying molecular drivers within this group of tumors, but clinical outcomes remain unchanged.

Summary: Here, we review the most recent molecular advances in pediatric ependymoma, evaluate results of recent clinical trials and discuss the ongoing challenges in the field and questions that remain.

Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome.

Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine.

ZFTA-RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma.

More than 60% of supratentorial ependymomas harbor a (ZR) gene fusion (formerly ). To study the biology of ZR, we developed an autochthonous mouse tumor model using electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZR tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZR-driven ependymoma.

Sub-group, Sub-type, and Cell-type Heterogeneity of Ependymoma.

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.

Targeting NAD Biosynthesis Overcomes Panobinostat and Bortezomib-Induced Malignant Glioma Resistance.

To improve therapeutic responses in patients with glioma, new combination therapies that exploit a mechanistic understanding of the inevitable emergence of drug resistance are needed. Intratumoral heterogeneity enables a low barrier to resistance in individual patients with glioma. We reasoned that targeting two or more fundamental processes that gliomas are particularly dependent upon could result in pleiotropic effects that would reduce the diversity of resistant subpopulations allowing convergence to a more robust therapeutic strategy.

BCOR-CCNB3 fusion-positive clear cell sarcoma of the kidney.

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.

Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas.

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.

Chromatin landscapes reveal developmentally encoded transcriptional states that define human glioblastoma.

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.

Pediatric ependymoma: current treatment and newer therapeutic insights.

Advances in genomic, transcriptomic and epigenomic profiling now identifies pediatric ependymoma as a defined biological entity. Molecular interrogation has segregated these tumors into distinct biological subtypes based on anatomical location, age and clinical outcome, which now defines the need to tailor therapy even for histologically similar tumors. These findings now provide reasons for a paradigm shift in therapy, which should profile future clinical trials focused on targeted therapeutic strategies and risk-based treatment.

Identification of alsterpaullone as a novel small molecule inhibitor to target group 3 medulloblastoma.

Advances in the molecular biology of medulloblastoma revealed four genetically and clinically distinct subgroups. Group 3 medulloblastomas are characterized by frequent amplifications of the oncogene MYC, a high incidence of metastasis, and poor prognosis despite aggressive therapy. We investigated several potential small molecule inhibitors to target Group 3 medulloblastomas based on gene expression data using an in silico drug screen.