Explore the vast range of titles available.

Pediatric diffuse intrinsic pontine glioma (DIPG) represents approximately 20% of all pediatric CNS tumors. However, disease outcomes are dismal with a median survival of less than 1 year and a 2-year overall survival rate of less than 10%. Despite extensive efforts to improve survival outcomes, progress towards clinical improvement has been largely stagnant throughout the last 4 decades. Focal radiotherapy remains the standard of care with no promising single-agent alternatives and no evidence for improvement with the addition of a long list of systemic therapies. A better understanding of the biology of DIPG, though not easy due to obstacles in obtaining pathological material to study, is promising for the development of specific individualized treatment for this fatal disease. Recent studies have found epigenetic mutations to be successful predictors and prognostic factors for developing future management policies. The aim of this review is to give a global overview about the epidemiology, diagnosis, and treatment of DIPG. We further examine the controversial biopsy and autopsy issue that is unique to DIPG and assess the subsequent impact this issue has on the research efforts and clinical management of DIPG.

Diffuse Midline Glioma (DMG), often formerly called Diffuse Intrinsic Pontine Glioma (DIPG) when in the brainstem, DMG/DIPG is a lethal pediatric brain tumor defined by infiltrative growth, resistance to conventional therapies, and a profound immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), including resident microglia and infiltrating monocyte-derived macrophages, are the predominant immune population in DMG/DIPG. These cells adopt an immunosuppressive, pro-tumor state, promoting immune evasion and limiting the efficacy of therapies such as chimeric antigen receptor (CAR) T cells. Reprogramming TAMs toward a pro-inflammatory, anti-tumor phenotype offers a promising strategy to remodel the DMG/DIPG microenvironment. This review is the first to provide a comprehensive, integrative perspective on TAM-directed strategies in DMG/DIPG, spanning molecular, epigenetic, and biophysical approaches. We summarize TAM-mediated tumor progression and therapy resistance, and discuss molecular reprogramming strategies, including colony-stimulating factor 1 receptor (CSF1R) inhibition, microRNA-based circuits, and epigenetic modulators such as histone deacetylase (HDAC) and bromodomain and extra-terminal domain (BET) inhibitors. Nanoparticle-mediated delivery systems allow selective TAM targeting and enhanced blood-brain barrier (BBB) penetration. Additional strategies, including oncolytic viruses and macrophage-specific checkpoint blockade (e.g., CD47/SIRPα axis inhibitors), simultaneously promote tumor clearance and immune activation. We also highlight emerging biophysical approaches to modulate TAM function in situ . Photodynamic therapy (PDT) induces immunogenic cell death and pro-inflammatory macrophage activity, while focused ultrasound (FUS) transiently disrupts the BBB to enhance drug delivery and immune infiltration. Photobiomodulation and low-level light therapy (LLLT) may influence macrophage metabolism and phenotype, though their application in DMG/DIPG remains largely unexplored. Finally, we discuss combinatorial strategies integrating TAM reprogramming with CAR T cell therapy or chemotherapy to overcome the immunologically “cold” nature of DMG/DIPG. By uniting mechanistic insights with translational opportunities, this review establishes TAM reprogramming as a critical, underexplored frontier in DMG/DIPG immunotherapy, offering the potential to render an otherwise intractable tumor immunologically targetable.

Recurrent, clonal somatic mutations in histone H3 are molecular hallmarks that distinguish the genetic mechanisms underlying pediatric and adult high-grade glioma (HGG), define biological subgroups of diffuse glioma, and highlight connections between cancer, development, and epigenetics. These oncogenic mutations in histones, now termed “oncohistones”, were discovered through genome-wide sequencing of pediatric diffuse high-grade glioma. Up to 80% of diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) and diffuse glioma arising in other midline structures including thalamus or spinal cord, contain histone H3 lysine 27 to methionine (K27M) mutations or, rarely, other alterations that result in a depletion of H3K27me3 similar to that induced by H3 K27M. This subgroup of glioma is now defined as diffuse midline glioma, H3K27-altered. In contrast, histone H3 Gly34Arg/Val (G34R/V) mutations are found in approximately 30% of diffuse glioma arising in the cerebral hemispheres of older adolescents and young adults, now classified as diffuse hemispheric glioma, H3G34-mutant. Here, we review how oncohistones modulate the epigenome and discuss the mutational landscape and invasive properties of histone mutant HGGs of childhood. The distinct mechanisms through which oncohistones and other mutations rewrite the epigenetic landscape provide novel insights into development and tumorigenesis and may present unique vulnerabilities for pHGGs. Lessons learned from these rare incurable brain tumors of childhood may have broader implications for cancer, as additional high- and low-frequency oncohistone mutations have been identified in other tumor types.

H3K27M diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like and AC-like phenotypes and perform transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs in the different cellular states. We then define strategies to target metabolic vulnerabilities within specific tumor populations. We show that AC-like cells exhibit a mesenchymal phenotype and are sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), and are accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors show efficacy and extend survival in preclinical orthotopic models established with stem-like H3K27M DMG cells. Together, this study demonstrates that cellular subtypes within DMGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain. Pediatric brain cancers are lethal malignancies driven by less-differentiated stem-like cells. Here the authors show that these cells exhibit distinct mitochondrial metabolism programs with targetable vulnerabilities.

Introduction Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. Methods Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. Results Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. Conclusion This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

Purpose We aimed to expand and refine the experimental models for pediatric-type diffuse high grade gliomas (pHGG) and the methods to follow up disease progression in mouse pHGG xenografts. Methods Using whole exome sequencing and immunoassays we characterized pHGG primary cultures and xenografts established at hospital SJD Barcelona. We obtained tumor samples and serial CSF samples from mouse xenografts. To assess tumor progression, we evaluated: (1) mouse weight, (2) human cell counts in brain paraffin sections, and (3) tumor DNA amount, quantified through droplet digital polymerase chain reaction (ddPCR) in paraffin sections and cerebrospinal fluid (CSF). Results We established 15 experimental models of three pHGG subclasses, four of which engrafted in mice. Xenografts HSJD-DIPG-007 and HSJD-DMG-005 are diffuse midline glioma (DMG) H3 K27-altered, HSJD-GBM-002 is an H3 G34-mutant diffuse hemispheric glioma, and HSJD-GBM-001 is an H3-wildtype and IDH-wildtype pHGG. ddPCR quantification of human H3F3A K27M, H3F3A G34R, and ACVR1 R206H in paraffin samples is linear and sufficiently sensitive. We required a preamplification step to detect H3F3A K27M in CSF. In HSJD-DIPG-007 xenografts, human cell counts correlated with H3F3A amounts in paraffin for the whole engraftment period. Weight loss correlated with human cell counts and H3F3A amounts in paraffin. Serial collection of CSF was feasible, but H3F3A amounts in the CSF correlated only with weight loss. Conclusion The developed methods contribute to the preclinical field of pHGG and introduce for the first time the concept of liquid biopsy in mice, which still needs improvement regarding its use as a preclinical biomarker.

Two single-center Phase I trials evaluated safety (primary endpoint) and preliminary efficacy (secondary endpoint) of oncolytic adenovirus Ad-TD-nsIL12 in primary (Group A, NCT05717712) and progressive (Group B, NCT05717699) pediatric patients with IDH wild-type (WT) diffuse intrinsic pontine glioma (DIPG). Studies employed single-arm and 3 + 3 dose-escalation design. 9 patients were enrolled in Group A and 6 in Group B. Group A completed the dose escalation, and no severe adverse events were observed. Enrollment in Group B was halted after Group A completed escalation. All patients experienced drug-related adverse events. In Group A, three partial responses and five stable diseases were documented, with a median overall survival (mOS) of 10.3 months after the first virus and 11.3 months after onset. In Group B, three patients had stable diseases, and three had progressive disease, with an mOS of 6.4 months after the first virus and 12.7 months after onset. Both groups demonstrated improved mOS from onset compared to the DIPG patients in our center’s retrospective study (mOS, 8.3 months). Both groups showed increased lymphocytes post-treatment, but only Group A decreased after radiotherapy. These trials confirmed the safety of Ad-TD-nsIL12 and provided preliminary efficacy evidence, offering insights for future clinical applications in DIPG. Bioelectronic sensors can use bacteria to detect toxins as electrical signals but are limited to single analytes. Here, the authors combine synthetic biology and electrochemistry to create a multi-channel bioelectronic sensor that detects multiple toxins and encodes digital output.

O -acetylated GD2 (OAcGD2) is a cancer-related antigen that is currently being explored for therapeutic use. Exploring the intricate mechanisms behind OAcGD2 synthesis in cancer cells has long been a challenge. Leveraging state-of-the-art high-throughput RNAi screening and confocal imaging technologies, our study delves into the genetic network orchestrating OAcGD2 synthesis in breast cancer cells. By conducting a comprehensive siRNA screen targeting the OAcGD2 phosphatome/kinome, we identified 43 genetic modulators, with 25 downregulating and 18 upregulating OAcGD2 synthesis. Among these, our study focused on CERK , the gene-encoding ceramide kinase, a pivotal player in glycosphingolipid metabolism. Through meticulous experimentation utilizing anti-CERK inhibitor and siRNAs, we made a significant discovery: CERK inhibition robustly upregulates OAcGD2 in both neuroblastoma and breast cancer cells, concurrently dampening cell migration. Furthermore, our findings highlight an exciting prospect: augmenting the antibody-dependent cell cytotoxicity of the chimeric human/mouse anti-OAcGD2 IgG1 monoclonal antibody (c8B6 mAb) against breast cancer and diffuse intrinsic pontine glioma cell lines in combination with specific CERK inhibitors. These results underscore the pivotal role of CERK inhibition in bolstering OAcGD2 synthesis, thus, presenting a promising strategy to increase the efficacy of anti-OAcGD2-based immunotherapy in patients with neuroectodermal tumors. By shedding light on this intricate interplay, our study paves the way for innovative therapeutic strategies poised to revolutionize the treatment landscape for these aggressive malignancies.

A total of 12 pediatric patients with diffuse intrinsic pontine glioma were treated with a direct infusion of an oncolytic virus, followed by radiotherapy. The tumor size was reduced in 9 patients, and disease was stable over a median follow-up of 18 months in 8 patients.

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor. While there are a number of in vivo rodent models for evaluating tumor biology and response to therapy, these models require significant time and resources. Here, we established the chick-embryo chorioallantoic (CAM) assay as an affordable and time efficient xenograft model for testing a variety of treatment approaches for DIPG. We found that patient-derived DIPG tumors develop in the CAM and maintain the same genetic and epigenetic characteristics of native DIPG tumors. We monitored tumor response to pharmaco- and radiation therapy by 3-D ultrasound volumetric and vasculature analysis. In this study, we established and validated the CAM model as a potential intermediate xenograft model for DIPG and its use for testing novel treatment approaches that include pharmacotherapy or radiation.