Checkpoint antibody receptor modified ARMed CAR T circumvents the suppressive immunome in GBM.

Introduction: Glioblastoma (GBM) remains a deadly cancer with non-curative upfront treatment of radiation, resection, and chemotherapy. Not only has the standard of care for GBM patients not improved significantly over the past decade, life expectancy is less than 18 months, with no standard second-line therapy. We previously developed a 2 generation 4-1BB co-stimulated chimeric antigen receptor (CAR) targeting tumor-specific variant of the epidermal growth factor receptor (EGFRvIII) for treating patients with GBM.

Single-dose radiotherapy is more effective than fractionation when combined with anti-PD-1 immunotherapy in glioblastoma.

Glioblastoma (GBM), the most common adult primary brain tumor, has an average survival of only 15-18 months. Recently, the combination of immune checkpoint blockers paired with radiotherapy has shown promise in preclinical murine GBM models. Human clinical trials have largely failed.

Machine learning-predicted chromatin organization landscape across pediatric tumors.

Structural variants (SVs) are increasingly recognized as important contributors to oncogenesis through their effects on 3D genome folding. Recent advances in whole-genome sequencing have enabled large-scale profiling of SVs across diverse tumors, yet experimental characterization of their individual impact on genome folding remains infeasible. Here, we leveraged a convolutional neural network, Akita, to predict disruptions in genome folding caused by somatic SVs identified in 61 tumor types from the Children's Brain Tumor Network dataset.

The radiogenomic and spatiogenomic landscapes of glioblastoma and their relationship to oncogenic drivers.

Background: Glioblastoma is a highly heterogeneous brain tumor, posing challenges for precision therapies and patient stratification in clinical trials. Understanding how genetic mutations influence tumor imaging may improve patient management and treatment outcomes. This study investigates the relationship between imaging features, spatial patterns of tumor location, and genetic alterations in IDH-wildtype glioblastoma, as well as the likely sequence of mutational events.

Immunoglobulin superfamily 3 (Igsf3) function is dispensable for brain development.

The Immunoglobulin superfamily (IgSF) is a heterogeneous and conserved family of adhesion proteins crucial during the development of the central nervous system including neuronal migration and synaptogenesis. The Immunoglobulin superfamily member 3 (IGSF3) is expressed in the developing brain and has been suggested to play a role during morphological development of the granule cells neurites in the cerebellum. In addition, a role for IGSF3 in supporting glioma progression has been recently demonstrated.

Designing a time-dependent therapeutic strategy using CDK4/6 inhibitors in an intracranial ATRT model.

Background: Inhibitors targeting cyclin-dependent kinases 4 and 6 (CDK4/6), crucial for cell cycle regulation, have shown promise in early-stage studies for treating central nervous system (CNS) tumors. However, challenges such as limited CNS penetration, optimal treatment duration, and systemic side effects have impeded their clinical translation for pediatric brain tumors (PBTs).

Methods: We evaluated the potency of CDK4/6 inhibitors across various PBT cell lines, focusing particularly on palbociclib against atypical teratoid rhabdoid tumor (ATRT) with cell viability assays and gene expression analysis.

The Genetics of Chiari 1 Malformation.

Chiari malformation type 1 (CM1) is a structural defect that involves the herniation of the cerebellar tonsils through the foramen magnum, causing mild to severe neurological symptoms. Little is known about the molecular and developmental mechanisms leading to its pathogenesis, prompting current efforts to elucidate genetic drivers. Inherited genetic disorders are reported in 2-3% of CM1 patients; however, CM1, including familial forms, is predominantly non-syndromic.

Influence of focused ultrasound on locoregional drug delivery to the brain: Potential implications for brain tumor therapy.

Introduction: Efficient delivery of therapeutics across the blood-brain barrier (BBB) for the treatment of central nervous system (CNS) tumors is a major challenge to the development of safe and efficacious therapies. Locoregional drug delivery platforms offer an improved therapeutic index by achieving high drug concentrations in the target tissue with negligible systemic exposure. Intrathecal (intraventricular) [IT] and convection-enhanced delivery [CED] are two clinically relevant methods being employed for various CNS malignancies.

Preclinical validation of a novel therapeutic strategy for choroid plexus carcinoma.

Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. Development of novel therapeutical strategies for this disease have been extremely limited owing to the rarity of the disease and the paucity of biologically relevant substrates. We conducted the first high-throughput screen (HTS) on a human patient-derived CPC cell line (Children Cancer Hospital Egypt, CCHE-45) and identified 427 top hits highlighting key molecular targets in CPC.

Leptomeningeal dissemination in pediatric brain tumors.

Leptomeningeal disease (LMD) in pediatric brain tumors (PBTs) is a poorly understood and categorized phenomenon. LMD incidence rates, as well as diagnosis, treatment, and screening practices, vary greatly depending on the primary tumor pathology. While LMD is encountered most frequently in medulloblastoma, reports of LMD have been described across a wide variety of PBT pathologies.

Developments in high-throughput functional epigenomics: CRISPR-single-cell assay for transposase-accessible chromatin using sequencing screens.

Tweetable abstract CRISPR-scATAC-seq screens pave the way for high-throughput functional epigenomics by linking perturbations to a broad view of epigenetic state and messages hidden within accessible sequences.

RP58 Represses Transcriptional Programs Linked to Nonneuronal Cell Identity and Glioblastoma Subtypes in Developing Neurons.

How mammalian neuronal identity is progressively acquired and reinforced during development is not understood. We have previously shown that loss of RP58 (ZNF238 or ZBTB18), a BTB/POZ-zinc finger-containing transcription factor, in the mouse brain leads to microcephaly, corpus callosum agenesis, and cerebellum hypoplasia and that it is required for normal neuronal differentiation. The transcriptional programs regulated by RP58 during this process are not known.

PET, image-guided HDAC inhibition of pediatric diffuse midline glioma improves survival in murine models.

Efforts at altering the dismal prognosis of pediatric midline gliomas focus on direct delivery strategies like convection-enhanced delivery (CED), where a cannula is implanted into tumor. Successful CED treatments require confirmation of tumor coverage, dosimetry, and longitudinal in vivo pharmacokinetic monitoring. These properties would be best determined clinically with image-guided dosimetry using theranostic agents.

Missing diversity in brain tumor trials.

Background: Clinical trials for brain tumors represent a significant opportunity for both patients and providers to understand and combat a disease with substantial morbidity. The aim of this study was to quantify and map ethnic and racial representation in brain tumor trials and examine the potential gaps in trial recruitment. We also show that these representation gaps persist even in large multicultural cities like New York City.

Multivariate Analysis of Preoperative Magnetic Resonance Imaging Reveals Transcriptomic Classification of Glioblastoma Patients.

Glioblastoma, the most frequent primary malignant brain neoplasm, is genetically diverse and classified into four transcriptomic subtypes, i. e., classical, mesenchymal, proneural, and neural.

B7-H3 as a Prognostic Biomarker and Therapeutic Target in Pediatric central nervous system Tumors.

B7-H3 (CD276), a member of the B7 superfamily, is an important factor in downregulating immune responses against tumors. It is also aberrantly expressed in many human malignancies. Beyond immune regulatory roles, its overexpression has been linked to invasive metastatic potential and poor prognosis in patients with cancer.

Immune landscapes associated with different glioblastoma molecular subtypes.

Recent work has highlighted the tumor microenvironment as a central player in cancer. In particular, interactions between tumor and immune cells may help drive the development of brain tumors such as glioblastoma multiforme (GBM). Despite significant research into the molecular classification of glioblastoma, few studies have characterized in a comprehensive manner the immune infiltrate in situ and within different GBM subtypes.

Transcriptome signatures associated with meningioma progression.

Meningiomas are the most common primary brain tumor of adults. The majority are benign (WHO grade I), with a mostly indolent course; 20% of them (WHO grade II and III) are, however, considered aggressive and require a more complex management. WHO grade II and III tumors are heterogeneous and, in some cases, can develop from a prior lower grade meningioma, although most arise de novo.

Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas.

We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial (ClinicalTrials.

In vivo evaluation of EGFRvIII mutation in primary glioblastoma patients via complex multiparametric MRI signature.

Background: Epidermal growth factor receptor variant III (EGFRvIII) is a driver mutation and potential therapeutic target in glioblastoma. Non-invasive in vivo EGFRvIII determination, using clinically acquired multiparametric MRI sequences, could assist in assessing spatial heterogeneity related to EGFRvIII, currently not captured via single-specimen analyses. We hypothesize that integration of subtle, yet distinctive, quantitative imaging/radiomic patterns using machine learning may lead to non-invasively determining molecular characteristics, and particularly the EGFRvIII mutation.

Radiomic MRI signature reveals three distinct subtypes of glioblastoma with different clinical and molecular characteristics, offering prognostic value beyond IDH1.

The remarkable heterogeneity of glioblastoma, across patients and over time, is one of the main challenges in precision diagnostics and treatment planning. Non-invasive in vivo characterization of this heterogeneity using imaging could assist in understanding disease subtypes, as well as in risk-stratification and treatment planning of glioblastoma. The current study leveraged advanced imaging analytics and radiomic approaches applied to multi-parametric MRI of de novo glioblastoma patients (n = 208 discovery, n = 53 replication), and discovered three distinct and reproducible imaging subtypes of glioblastoma, with differential clinical outcome and underlying molecular characteristics, including isocitrate dehydrogenase-1 (IDH1), O-methylguanine-DNA methyltransferase, epidermal growth factor receptor variant III (EGFRvIII), and transcriptomic subtype composition.

Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α.

Spatiotemporal regulation of tumor immunity remains largely unexplored. Here we identify a vascular niche that controls alternative macrophage activation in glioblastoma (GBM). We show that tumor-promoting macrophages are spatially proximate to GBM-associated endothelial cells (ECs), permissive for angiocrine-induced macrophage polarization.

Rapid Chromatin Switch in the Direct Reprogramming of Fibroblasts to Neurons.

How transcription factors (TFs) reprogram one cell lineage to another remains unclear. Here, we define chromatin accessibility changes induced by the proneural TF Ascl1 throughout conversion of fibroblasts into induced neuronal (iN) cells. Thousands of genomic loci are affected as early as 12 hr after Ascl1 induction.

SHP2 regulates proliferation and tumorigenicity of glioma stem cells.

SHP2 is a cytoplasmic protein tyrosine phosphatase (PTPase) involved in multiple signaling pathways and was the first identified proto-oncogene PTPase. Previous work in glioblastoma (GBM) has demonstrated the role of SHP2 PTPase activity in modulating the oncogenic phenotype of adherent GBM cell lines. Mutations in PTPN11, the gene encoding SHP2, have been identified with increasing frequency in GBM.