Search Results (73)

Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brainstem malignancy for which effective treatment options are lacking. Cerebrospinal fluid (CSF) analysis can reveal intrinsic alterations and characteristic metabolic profiles of the tumor microenvironment. In this study, the proteome and metabolome of CSF from DIPG patients were comprehensively analyzed to identify potential biomarkers and the pathways involved. Functional annotation and pathway enrichment analyses were performed using the GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) databases. Bioinformatics methods were used to comprehensively analyze the proteomic and metabolomic results to identify key differentially expressed proteins, metabolites, and potential signaling pathways involved in DIPG. In total, 885 DEPs (differentially expressed proteins) were identified in cerebrospinal fluid from DIPG patients, of which 54 were upregulated and 831 were downregulated, primarily originating from the cytoplasm and cell membrane. Among the top 20 upregulated proteins, URB1 (nucleolar pre-ribosomal-associated protein 1) had the greatest statistical significance, while the remaining proteins were mostly immunoglobulin fragments. GO enrichment analysis revealed that the downregulated proteins were enriched primarily in cellular processes, metabolic processes, and binding functions. KEGG analysis revealed that upregulated proteins were significantly enriched in complement and coagulation cascades, whereas downregulated proteins were primarily associated with endocytosis and certain microbial infections. A total of 1372 metabolites were identified, of which 40 were differentially expressed: 24 were upregulated, and 16 were downregulated. Pathway analyses of the differentially expressed metabolites revealed that they were primarily related to purine metabolism and tyrosine metabolism. The multiomics analysis revealed that purine metabolism is particularly important in DIPG. Full article

Nimotuzumab is a humanized anti-EGFR monoclonal antibody with a unique pharmacodynamic profile characterized by intermediate affinity and bivalent binding dependence, enabling density-selective tumor targeting while sparing normal tissues from the severe skin rash and other toxicities common to EGFR inhibitors. Since its first approval in 2002, nimotuzumab has been registered for eight cancer indications. Unlike conventional fixed-dose schedules, emerging evidence supports prolonged administration beyond initial combination therapy. This review summarizes clinical data from pancreatic cancer, esophageal cancer, high-grade glioma, pediatric diffuse intrinsic pontine glioma, head and neck squamous cell carcinoma, nasopharyngeal cancer and other solid tumors, showing that extended nimotuzumab exposure, often as maintenance monotherapy, may prolong overall survival, progression-free survival, and disease control compared to limited cycles. Despite heterogeneity in tumor types and treatment regimens, maintenance nimotuzumab was consistently associated with better results, particularly in terms of overall survival. Notably, significant survival benefits were observed in locally advanced SCCHN (24.9 vs. 12.5 months) and esophageal cancer (15.9 vs. 8.1 months) across independent clinical trials. Mechanistically, nimotuzumab exerts direct cytostatic effects via G1 arrest, potent anti-angiogenic activity through VEGF downregulation, indirect pro-apoptotic effects, and broad immunomodulation including ADCC, NK-DC cross-talk, EGFR-specific CD8+ T cell priming, upregulation of HLA class I, and favorable regulation of regulatory T cells. Its density-selective binding reduces selective pressure for acquired resistance. Future research priorities should include prospective randomized trials specifically evaluating maintenance strategies, biomarker-driven patient selection, the molecular characterization of resistance mechanisms, integration with immunotherapy and modern combination regimens, and the development of next-generation platforms, including antibody–drug conjugates and multi-specific constructs. Full article

We analyze data indicating that a set of currently marketed FDA/EMA-approved drugs used to treat parkinsonism, extrapyramidal side effects of antipsychotic drugs, or overactive bladder may have the potential to slow the growth of glioblastoma; diffuse midline glioma, H3K27-altered (DMG); and a particular form of DMG growing in the pons of children, diffuse intrinsic pontine glioma (DIPG). These gliomas are typically associated with poor prognosis. Clinical trials evaluating conventional chemotherapeutic drugs have failed to improve DIPG survival. Our analysis of the biochemistry and physiology of DMG and DIPG concludes that neuronal acetylcholinergic agonisms at muscarinic receptors M1 and M3 on primitive oligodendrocyte precursor cells (OPCs) are trophic, growth-stimulating factors in DMG/DIPG growth. A set of muscarinic receptor inhibitors—benztropine, biperiden, and trihexyphenidyl—is used clinically to treat Parkinson’s disease or the parkinsonian side effects from antipsychotic medicines. Another muscarinic inhibitor, oxybutynin, is used to treat overactive bladder. All four drugs may impose dose-related side effects inherent to muscarinic receptor inhibition, such as xerostomia, asthenia, and mild cognitive impairment. We recount the evidence for the inhibition of OPC proliferation and migration mediated by these four M1/M3 inhibitors and report details on the rationale for selecting oxybutynin as the primary candidate for adjuvant therapy in DMG/DIPG. We chose oxybutynin as the first choice to study in DMG and DIPG compared to other antimuscarinic drugs based on its (i) high brain-tissue concentration, (ii) relatively stronger M3 inhibition, (iii) lower side-effect propensity than scopolamine, (iv) wide availability, and (v) the absence of H1 antihistamine or dopaminergic effects. Given the rapidly fatal nature of DMG and DIPG, the potential of oxybutynin for growth slowing may outweigh the associated risks and mild side-effect burdens. Full article

Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brain tumor. Radiotherapy remains the standard of care, but tumors recur due to radioresistance. Tumor hypoxia contributes to radioresistance, and evidence of oxidative metabolism and hypoxia-associated transcriptomic programs suggests that hypoxia may be relevant in DIPG. We therefore investigated the FDA-approved mitochondrial inhibitor atovaquone as a strategy to target oxidative metabolism and enhance radiation response in DIPG. Methods: Patient-derived DIPG cell lines were used to evaluate atovaquone by extracellular flux analysis, hypoxia and reactive oxygen species assays, clonogenic survival assays, metabolomics, and RNA sequencing. To improve brain exposure, an amorphous solid dispersion (ASD) atovaquone formulation was evaluated and tested in an orthotopic DIPG model. Results: In patient-derived DIPG cultures, atovaquone suppressed mitochondrial respiration, reduced hypoxia-associated readouts, decreased HIF-1α expression in 3D models, and enhanced radiation response. At higher concentrations, atovaquone also increased oxidative stress and enhanced the radiosensitivity of DIPG monolayers. Transcriptomics analysis revealed disruption of cell-cycle and mitotic pathways, supporting additional treatment-associated effects beyond hypoxia reduction alone. Commercial and ASD formulations showed comparable in vitro activity. In vivo, ASD atovaquone combined with radiation prolonged survival in an orthotopic DIPG model. Conclusions: Targeting mitochondrial metabolism enhances radiosensitivity in DIPG and supports mitochondrial metabolism as a potential therapeutic weakness in this disease. Its effects are associated with reduced hypoxia-related signaling and broader metabolic and transcriptional changes. Full article

Tyrosine kinases (TKs) are drug targets in diffuse intrinsic pontine glioma (DIPG). Ion channels are emerging targets in cancer. TKIs targeting different kinases such as everolimus, crizotinib, dasatinib, erlotinib, lapatinib, perifosine and midostaurin (0.001–100 μM) were investigated on cell proliferation and ion channel currents. Methods: Cell viability assays in parallel with a patch-clamp study and Western blot of target proteins are performed in SU-DIPG-36 and SU-DIPG-50 cells. Results: Midostaurin is the most effective drug in different assays. Patch-clamp investigations show that the application of midostaurin reduced the inward and outward whole-cell cation channel currents vs. controls in the presence of low internal ATP. These currents were sensitive to the KATP channel inhibitors glibenclamide and repaglinide and were fully reduced by the unselective blocker TEA-BaCl₂. Midostaurin also reduced currents that are sensitive to TRPV1 channel blockers capsazepine and ruthenium-red. The IC₅₀ values of midostaurin as an antiproliferative drug and ion channel inhibitor in either cell line are in the sub-micromolar range. In SU-DIPG-36 cells midostaurin causes a concentration-dependent upregulation of autophagy markers. Conclusions: The inhibition of cation channel currents by midostaurin in SU-DIPG-36 and SU-DIPG-50 cells and the autophagy potentiation in SU-DIPG-36 cells can be novel mechanisms in DIPG. Full article

Background: Lentiviral vectors (LVs) show promise as gene therapy tools for brain tumors, but optimal envelope protein choices for different tumor types have not been determined. Methodology: This study evaluated three pseudotyped LV variants—VSV-GP, FuG-B2, and LCMV-GP—across diverse brain tumor cell lines including glioblastoma (GBM), diffuse intrinsic pontine glioma (DIPG), medulloblastoma, and metastatic brain cancers. Results: VSV-GP and FuG-B2 pseudotypes significantly outperformed LCMV-GP across most tumor types. Both VSV-GP and FuG-B2 demonstrated high transduction efficiency in GBM and DIPG cells, though some cell lines displayed selective preferences for one pseudotype over the other. Medulloblastoma cells were challenging to transduce, with only VSV-GP achieving substantial efficacy. Metastatic brain cancers showed distinct tropism patterns: melanoma metastases were preferentially transduced by the FuG-B2 pseudotype, while lung metastases showed preference for the VSV-GP pseudotype. Conclusions: These findings suggest envelope protein selection should be tailored to specific brain tumor types. VSV-GP appears most suitable for medulloblastoma and lung metastases, FuG-B2 for melanoma metastases, and both for GBM and DIPG gene therapy applications. The study provides crucial guidance for translating lentiviral gene therapy to clinical applications, supporting personalized treatment strategies based on tumor-specific vector tropism profiles. Full article

Diffuse intrinsic pontine glioma (DIPG), or as it is newly redefined, diffuse midline glioma (DMG), remains one of the most horrific diagnoses in pediatric oncology. Aggressive and inaccessible to standard treatments, it is generally considered incurable. Focused ultrasound technology has developed over the last several decades as a noninvasive means to target various types of tumors in both adults and children. Recent advances, particularly in low-intensity focused ultrasound (LIFU), have opened new avenues for enhancing drug delivery and modulating the tumor microenvironment in these challenging tumors. This review provides a comprehensive overview of preclinical and clinical research developments in the use of LIFU for pediatric DMGs. We highlight key findings from animal models demonstrating improved blood–brain barrier (BBB) permeability, increased chemotherapeutic and nanoparticle delivery, and potential immunomodulatory effects of LIFU. Emerging clinical studies, including early-phase safety and feasibility trials, are also discussed, with attention to technical parameters, imaging guidance strategies, and biomarkers of response. The review concludes by addressing the challenges of translating LIFU into routine clinical practice, including device optimization for pediatric anatomy, regulatory hurdles, and the need for standardized treatment protocols. Collectively, these recent advances underscore the promise of LIFU as a minimally invasive, image-guided adjunct to current and future therapies for pediatric DMGs, warranting continued research and collaborative clinical efforts. Full article

Bevacizumab is often used off-label in pediatric neuro-oncology, and evidence for indications of bevacizumab use in pediatric neuro-oncology is often fragmented. Therefore, this review aims to provide an organized summary of efficacy across different types of tumors, highlight outcomes, and link findings to the underlying biology. Gaps in the literature were also identified to guide future research. We narratively synthesized various pediatric studies, and the following tumor categories were identified for discussion: low-grade glioma, high-grade glioma, diffuse intrinsic pontine glioma, schwannoma, medulloblastoma, radiation necrosis, and cerebral edema. Key outcomes considered included overall survival, event-free survival, progression-free survival, vision and/or hearing improvements, steroid use, quality of life, and toxicity. The greatest benefits were observed in cases such as recurrent medulloblastoma in combination with temozolomide and irinotecan, optic pathway glioma visual function, and diminished steroid use in radiation necrosis. Results were poorer in cases of newly diagnosed high-grade gliomas and diffuse intrinsic pontine gliomas. The medication was overall well tolerated, with adverse events like hypertension, proteinuria, and epistaxis often being manageable with surveillance. In consideration of the results, bevacizumab should be considered based on the tumor profile, and its outcome measured along functional endpoints, besides radiological evolution. Continued investigations into outcome measures, as well as combination with targeted treatments and optimizing therapy, will contribute to improving outcomes in this vulnerable population. Full article

Pediatric central nervous system (CNS) tumors, including gliomas, medulloblastomas, and diffuse midline gliomas (previously diffuse intrinsic pontine gliomas), remain a major clinical challenge due to their complex biology, limited treatment effectiveness, and generally poor prognosis. Standard treatments are often aggressive and associated with substantial toxicity, particularly in advanced stages. This review highlights recent developments in radiopharmaceuticals for molecular imaging and targeted radiotherapy. A comprehensive literature analysis was conducted, focusing on radiotracers with clinical relevance in pediatric neuro-oncology, including metabolic, peptide receptor-based, and antibody-based agents. Radiopharmaceuticals such as ¹⁸F-FLT, ⁶⁴CuCl₂, and 1-L-18F-FETrp have improved the ability to monitor tumor biology, proliferation, and treatment response, aiding in diagnosis at an early stage, assessment of tumor behavior, and detection of recurrence or progression. Additionally, peptide receptor-based radiotracers, such as ⁶⁸Ga-DOTATATE and ¹⁷⁷Lu-DOTATATE, are already used for both diagnostic purposes and targeted radiotherapy, particularly in neuroblastomas and gliomas. Antibody-based radiotracers like ¹³¹I-omburtamab, targeting B7-H3, are emerging as promising tools for addressing difficult-to-treat tumors such as diffuse midline glioma. Collectively, these advances provide new hope for children afflicted by these devastating malignancies, offering promising solutions for more specific and precise diagnosis and, additionally, for more effective, personalized, and less toxic tumor therapies. Full article

Background: The blood–brain barrier (BBB) plays an important role in regulating homeostasis of the central nervous system (CNS), and it is an obstacle for molecules with a molecular weight higher than 500 Da seeking to reach it, making many drugs ineffective simply because they cannot be delivered to where they are needed. As a result, crossing the BBB remains the rate-limiting factor in brain drug delivery during the treatment of brain diseases, specifically tumors such as diffuse intrinsic pontine glioma (DIPG), a highly aggressive pediatric tumor with onset in the pons Varolii, the middle portion of the three contiguous parts of the brainstem, located above the medulla and below the midbrain. Methods: Currently, radiotherapy (RT) relieves DIPG symptoms but chemotherapy drugs do not lead to significant results as they do not easily cross the BBB. Focused ultrasound (FUS) and microbubbles (MBs) can temporarily open the BBB, facilitating radiotherapy and the entry of drugs into the CNS. A patient-derived xenograft DIPG model exposed to high-intensity focalized ultrasound (HIFU) or low-intensity focalized ultrasound (LIFU) combined with MBs was treated with doxorubicin, panobinostat, olaparib, ONC201 (Dordaviprone^®) and anti-PD1. Panobinostat has also been used in children with diffuse midline glioma, a broad class of brain tumors to which DIPG belongs. Results: Preliminary studies were performed using FUS to temporarily open the BBB and allow a milder use of radiotherapy and facilitate the passage of drugs through the BBB. The data collected show that after opening the BBB with FUS and MBs, drug delivery to the CNS significantly improved. Conclusions: FUS associated with MBs appears safe and feasible and represents a new strategy to increase the uptake of drugs in the CNS and therefore enhance their effectiveness. This review reports pre-clinical and clinical studies performed to demonstrate the usefulness of FUS in patients with DIPG treated with some chemotherapy. The papers reviewed were published in PubMed until the end of 2024 and were found using a combination of the following keywords: diffuse intrinsic pontine glioma (DIPG), DIPG H3K27-altered, blood–brain barrier and BBB, focused ultrasound (FUS) and radiotherapy (RT). Full article

Background: ATRTs and DIPGs are deadly pediatric brain tumors with poor prognosis. These tumors can develop resistance to chemotherapies, which may be significantly influenced by their microenvironment. Since astrocytes are the most abundant glial cell type in the brain microenvironment and may support tumor growth and chemoresistance, this study investigated the effects of induced pluripotent stem cell-derived astrocytes (iPSC-astrocytes) on cisplatin sensitivity in CHLA-05-ATRT and SF8628 (DIPG) cells. iPSCs provide an unlimited and standardized source of nascent astrocytes, which enables modeling the interaction between childhood brain tumor cells and iPSC-astrocytes within a controlled coculture system. Methods: To study the effects on tumor growth, the iPSC-astrocytes were cocultured with tumor cells. Additionally, the tumor cells were exposed to various concentrations of cisplatin to evaluate their chemosensitivity in the presence of astrocytes. Results: The paracrine interaction of iPSC-astrocytes with tumor cells upregulated astrocyte activation markers GFAP and STAT3 and promoted tumor cell proliferation. Moreover, the cisplatin treatment significantly decreased the viability of CHLA-05-ATRT and SF8628 cells. However, tumor cells exhibited reduced sensitivity to cisplatin in the coculture with iPSC-astrocytes. During cisplatin treatment, DIPG cells in particular showed upregulation of resistance markers, ERK1, STAT3, and MTDH, which are associated with enhanced proliferation and invasion. They also had increased expression of APEX1, which is involved in the base excision repair pathway following cisplatin-induced DNA damage. Conclusion: These findings underscore the significance of the tumor microenvironment in modulating tumor cell survival and chemosensitivity. Full article

Diffuse intrinsic pontine glioma (DIPG) is a rare but extremely malignant central nervous system tumor primarily affecting children that is almost universally fatal with a devastating prognosis of 8-to-12-month median survival time following diagnosis. Traditionally, DIPG has been diagnosed via MR imaging alone and treated with palliative radiation therapy. While performing surgical biopsies for these patients has been controversial, in recent years, advancements have been made in the safety and efficacy of surgical biopsy techniques, utilizing stereotactic, robotics, and intraoperative cranial nerve monitoring as well as the development of liquid biopsies that identify tumor markers in either cerebrospinal fluid or serum. With more molecular data being collected from these tumors due to more frequent biopsies being performed, multiple treatment modalities including chemotherapy, radiation therapy, immunotherapy, and epigenetic modifying agents continue to be developed. Numerous recent clinical trials have been completed or are currently ongoing that have shown promise in extending survival for patients with DIPG. Focused ultrasound (FUS) has also emerged as an additional promising adjunct invention used to increase the effectiveness of therapeutic agents. In this review, we discuss the current evidence to date for these advancements in the diagnosis and treatment of DIPG. Full article

Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating childhood brainstem tumor. The median survival of DIPG is 16–24 months independent of the treatment received. Therefore, new therapeutic strategies against DIPG are urgently needed. Substance P (SP) peptide, through the neurokinin neurokinin-1 receptor (NK-1R), is involved in glioma progression. It induces glioma cell proliferation by activating MAPKs (p38 MAPK, ERK1/2, and JNK), c-Myc, AP-1, and NF-κB and induces antiapoptotic effects via PI3K/Akt/mTOR in glioma cells. SP favors glycogen breakdown that is essential for glycolysis. The SP/NK-1R system also regulates the migration and invasion of glioma cells, stimulates angiogenesis, and triggers inflammation which contributes to glioma progression. Moreover, all glioma cells express NK-1R, and NK-1R is essential for the viability of glioma cells and not of normal cells. In contrast, in glioma, NK-1R antagonists, such as the drug aprepitant, penetrate the brain and reach therapeutic concentrations, thereby inhibiting mitogenesis, inducing apoptosis, and inhibiting the breakdown of glycogen in glioma cells. In addition, they inhibit angiogenesis and exert antimetastatic and anti-inflammatory effects. The combination of radiotherapy with NK-1R antagonists produces radiosensitization and radioneuroprotection, reduces both peritumoral- and radiation-induced inflammation, and also provides antinausea and antivomiting effects. Objective: This review updates the involvement of the SP/NK-1R system in glioma promotion and progression and the potential clinical application of NK-1R antagonist drugs in DIPG therapy. Conclusions: NK-1R plays a crucial role in glioma progression and NK-1R antagonists such as aprepitant could be used in combination with radiotherapy as a potent therapeutic strategy for the treatment of patients with DIPG. Full article

Background: It is unclear as to where we stand with respect to utilizing emerging focused ultrasound (FUS) technology in the setting of brain tumor treatment in pediatric patients, such as malignant diffuse intrinsic pontine glioma, and various adult counterparts. Correspondingly, the aim of this study was to present a contemporary summary of all pertinent clinical trials to date. Methods: The ClinicalTrials.gov database was reviewed in January 2025 for all possible clinical trials involving FUS in the management of brain tumors. These were then screened against selection criteria to identify pertinent clinical trials. Results: A total of 30 clinical trials were identified. The majority were focused on adult patients (24/30, 80%), with the most common tumor type being glioblastoma (GBM) (14/30, 47%). There were also trials focused on pediatric patients only (5/30, 17%), as well as diffuse intrinsic pontine glioma (DIPG) (5/30, 17%). The most prevalent primary outcome of interest was safety (26/30, 87%). The majority of trials were active, either recruiting currently (12/30, 40%), or active but not recruiting currently (3/30, 10%). North America (22/30, 73%) was the most common location for the primary coordinating institution, and the median number of institutions per trial was one. The median expected start year for all trials was 2021, and the completion year was 2024. To date, there have been no results (interim or final) formally reported, although preliminary reports in the literature indicate this to be a safe procedure. Anecdotal trends suggest later trials target the blood-brain barrier more, involve more pediatric patients, and are more based in the United States. Conclusion: There exists a number of early-stage clinical trials investigating FUS to treat a variety of brain tumors in pediatric patients, as well as adult patients, with a significant clinical potential to improve outcomes. To date, no official results have been published, however anecdotal evidence is promising, and a number of results are expected soon. Full article

Despite recent advancements in radiotherapy for Diffuse Intrinsic Pontine Glioma (DIPG), the prognosis of this disease remains poor, highlighting the need for new treatment strategies to improve outcomes. Adding stereotactic biopsy to the diagnostic process for children with DIPG has been crucial in improving the management of this disease. Indeed, the discovery of the H3K27M mutation as a key driver of DIPG has led to the development of new drugs that are more effective than traditional ones. These include nimotuzumab (an anti-EGFR drug) and vinorelbine (a semisynthetic vinca alkaloid) in combination, Panobinostat (a histone deacetylase inhibitor), ONC201 (a drug that blocks the dopamine receptor D2 and inactivates Akt and ERK kinases), and chimeric antigen receptor (CAR) T cells. In terms of local therapy, identifying the H3K27M mutation can help us explore how genetic changes affect treatment response, recurrence patterns, and survival. Beyond the time to first recurrence, specific patterns of tumor recurrence, like leptomeningeal spread, can influence treatment plans. For example, radiotherapy can be adjusted in terms of doses and volumes, based on tumor aggressiveness. Because the H3K27M mutation is linked to higher malignancy, a slightly higher dose could be used for the second round of local irradiation. Additionally, irradiating the entire craniospinal axis could help control both local and leptomeningeal disease. Full article