Glioma Therapy Research Articles

Polyamidoamine Dendrimers: Brain-Targeted Drug Delivery Systems in Glioma Therapy.

Glioma is the most common primary intracranial tumor, which is formed by the malignant transformation of glial cells in the brain and spinal cord. It has the characteristics of high incidence, high recurrence rate, high mortality and low cure rate. The treatments for glioma include surgical removal, chemotherapy and radiotherapy. Due to the obstruction of the biological barrier of brain tissue, it is difficult to achieve the desired therapeutic effects. To address the limitations imposed by the brain's natural barriers and enhance the treatment efficacy, researchers have effectively used brain-targeted drug delivery systems (DDSs) in glioma therapy. Polyamidoamine (PAMAM) dendrimers, as branched macromolecular architectures, represent promising candidates for studies in glioma therapy. This review focuses on PAMAM-based DDSs in the treatment of glioma, highlighting their physicochemical characteristics, structural properties as well as an overview of the toxicity and safety profiles.

Advances in two-photon absorption photodynamic therapy of glioma based on porphyrin-based metal-organicframework composites

Gliomas of the brain are characterised by high aggressiveness, high postoperative recurrence rate, high morbidity and mortality, posing a great challenge to clinical treatment. Traditional treatments include surgery, radiotherapy and chemotherapy; they also have significant associated side effects, leading to difficulties in tumour resection and recurrence. Photodynamic therapy has been shown to be a promising new strategy to help treat malignant tumours of the brain. It irradiates the tumour site at a specific wavelength to activate a photosensitiser, which selectively accumulates at the tumour site, triggering a photochemical reaction that destroys the tumour cells. It has the advantages of being minimally invasive, highly targeted and with few adverse reactions, and is expected to be well used in anti-tumour therapy. However, the therapeutic effect of traditional PDT is limited by the weak tissue penetration ability of photosensitiser, hypoxia and immunosuppression in the tumour microenvironment. This paper reviews the current research status on the therapeutic principle of photodynamic therapy in glioma and the mechanism of tumour cell injury, and also analyses the advantages and disadvantages of the current application in glioma treatment, and clarifies the analysis of ideas to improve the tissue penetration ability of photosensitizers. It aims to provide a feasible direction for the improvement of photodynamic therapy for glioma and a reference for the clinical treatment of deep brain tumours.

IDH1-mutant metabolite D-2-hydroxyglutarate inhibits proliferation and sensitizes glioma to temozolomide via down-regulating ITGB4/PI3K/AKT

The heterogeneous molecular subtypes of gliomas demonstrate varied responses to chemotherapy and distinct prognostic outcomes. Gliomas with Isocitrate dehydrogenase 1 (IDH1) mutation are associated with better outcomes and are more responsive to temozolomide (TMZ) compared to those without IDH1 mutation. IDH1-mutant gliomas elevate D-2-hydroxyglutarate (D-2HG) levels, with potential dual effects on tumor progression. Limited research has explored the potential anti-glioma effects of D-2HG in combination with TMZ. Clinical data from over 2500 glioma patients in our study confirms that those with IDH1 mutations exhibit enhanced responsiveness to TMZ chemotherapy and a significantly better prognosis compared to IDH1 wild-type patients. In subsequent cellular experiments, we found that the IDH1-mutant metabolite D-2HG suppresses Integrin subunit beta 4 (ITGB4) expression, and down-regulate the phosphorylation levels of PI3K and AKT, ultimately inhibiting cell proliferation while promoting apoptosis, thereby improving glioma prognosis. Additionally, we have demonstrated the synergistic effect of D-2HG and TMZ in anti-glioma therapy involved inhibiting the proliferation of glioma cells and promoting apoptosis. Finally, by integrating data from the CGGA and TCGA databases, it was validated that ITGB4 expression was lower in IDH1-mutant gliomas, and patients with lower ITGB4 expression were associated with better prognosis. These findings indicate that ITGB4 may be a promising therapeutic target for gliomas and D-2HG inhibits proliferation and sensitizes glioma to temozolomide via down-regulating ITGB4/PI3K/AKT. These findings drive theoretical innovation and research progress in glioma therapy.

Current standards and the future role of hadrontherapy in the treatment of central nervous system tumors

IntroductionRadiation therapy is vital for treating central nervous system cancers (CNS), but traditional methods have limitations, especially in cases with high risks of side effects. Ion beam therapy, with its unique properties, offers a promising alternative for more precise and effective treatment, particularly in challenging scenarios.Materials and methodsThe presentation given at the symposium on hadrontherapy covered relevant literature for the utilization of ion beam therapy for pediatric CNS tumors, glioma, and meningeoma, as well as its role in re-irradiation. Emphasis was placed on new beam modalities, including carbon and helium ions, highlighting their potential benefits in improving treatment outcomes.ResultsThe results underscore the importance of preserving surrounding healthy tissue in pediatric malignancies’ radiation therapy. Proton irradiation achieves optimal target coverage while reducing radiation-induced side effects. Carbon ions show promise in glioma treatment, with ongoing trials validating their efficacy. Moreover, helium ion therapy demonstrates advantages in sparing normal tissue, making it a promising candidate for reintroduction into clinical routines. These findings highlight the potential of ion beam therapies in optimizing treatment outcomes while minimizing side effects, particularly in pediatric CNS tumors and gliomas.ConclusionResults support proton therapy for brain tumors, aiming to preserve cognitive function. Carbon ions could benefit select patients in primary treatment and for recurrent cases. Helium ion therapy combines advantages of protons and carbon ions, offering precise dose deposition and tissue sparing, making it suitable for clinical use.

Brain-targeting biomimetic disguised manganese dioxide nanoparticles via hybridization of tumor cell membrane and bacteria vesicles for synergistic chemotherapy/chemodynamic therapy of glioma

Glioma is a prevalent brain malignancy associated with poor prognosis. Although chemotherapy serves as the primary treatment for brain tumors, its effectiveness is hindered by the limited ability of drugs to traverse the blood–brain barrier (BBB) and the development of drug resistance linked to tumor hypoxia. Herein, we report the creation of hybrid camouflaged multifunctional nanovesicles comprising membranes of tumor C6 cells (mT) and bacterial outer membrane vesicles (OMVs) and co-loaded with manganese dioxide nanoparticles (MnO2 NPs) and doxorubicin (DOX) to synergistically enhance the chemotherapy/chemodynamic therapy (CDT) of glioma. Owing to OMV-mediated BBB penetration and mT-inherited tumor-homing properties, MnO2-DOX@mT/OMVs can penetrate the BBB and enhance the tumor cell-specific uptake of DOX via “proton sponge effect”-mediated lysosomal escape. This enhances the apoptotic effect induced by DOX and minimizing DOX-associated cardiotoxicity by facilitating the accumulation of DOX at the tumor site. Furthermore, the MnO2 NPs in MnO2-DOX@mT/OMVs can generate potent CDT by accelerating the Fenton-like reaction with DOX-generated H2O2 and achieving glutathione (GSH)-depletion-induced glutathione peroxidase 4 (GPX4) inactivation. These results showed that MnO2-DOX@mT/OMVs, designed for brain tumor targeting, significantly inhibited tumor growth and exhibited favorable biological safety. This innovative approach offers the augmentation of anticancer treatment efficacy via a potential combination of chemotherapy and CDT.

Sequential intravenous and intracerebroventricular GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas.

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the GD2 disialoganglioside and chimeric antigen receptor modified T-cells targeting GD2 (GD2-CART) eradicate DMGs in preclinical models. Arm A of the Phase I trial NCT04196413 administered one IV dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline glioma at two dose levels (DL1=1e6/kg; DL2=3e6/kg) following lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) GD2-CART infusions (10-30e6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability, and identification of a maximally tolerated dose of IV GD2-CART. Secondary objectives included preliminary assessments of benefit. Thirteen patients enrolled and 11 received IV GD2-CART on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CART manufacturing was successful for all patients. No dose-limiting toxicities (DLTs) occurred on DL1, but three patients experienced DLT on DL2 due to grade 4 cytokine release syndrome (CRS). Nine patients received ICV infusions, which were not associated with DLTs. All patients exhibited tumor inflammation-associated neurotoxicity (TIAN). Four patients demonstrated major volumetric tumor reductions (52%, 54%, 91% and 100%). One patient exhibited a complete response ongoing for >30 months since enrollment. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score. Sequential IV followed by ICV GD2-CART induced tumor regressions and neurological improvements in patients with DIPG and sDMG. DL1 was established as the maximally tolerated IV GD2-CART dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.

WZ-3146 acts as a novel small molecule inhibitor of KIF4A to inhibit glioma progression by inducing apoptosis

BackgroundGlioma is considered the most common primary malignant tumor of the central nervous system. Although traditional treatments have not achieved satisfactory outcomes, recently, targeted therapies for glioma have shown promising efficacy. However, due to the single-target nature of targeted therapy, traditional targeted therapies are ineffective; thus, novel therapeutic targets are urgently needed.MethodsThe gene expression data for glioma patients were derived from the GEO (GSE4290, GSE50161), TCGA and CGGA databases. Next, the upregulated genes obtained from the above databases were cross-analyzed, finally, 10 overlapping genes (BIRC5, FOXM1, EZH2, CDK1, KIF11, KIF4A, NDC80, PBK, RRM2, and TOP2A) were ultimately screened and only KIF4A expression has the strongest correlation with clinical characteristics in glioma patients. Futher, the TCGA and CGGA database were utilized to explore the correlation of KIF4A expression with glioma prognosis. Then, qRT-PCR and Western blot was used to detect the KIF4A mRNA and protein expression level in glioma cells, respectively. And WZ-3146, the small molecule inhibitor targeting KIF4A, were screened by Cmap analysis. Subsequently, the effect of KIF4A knockdown or WZ-3146 treatment on glioma was measured by the MTT, EdU, Colony formation assay and Transwell assay. Ultimately, GSEA enrichment analysis was performed to find that the apoptotic pathway could be regulated by KIF4A in glioma, in addition, the effect of WZ-3146 on glioma apoptosis was detected by flow cytometry and Western blot.ResultsIn the present study, we confirmed that KIF4A is abnormally overexpressed in glioma. In addition, KIF4A overexpression is a key indicator of glioma prognosis; moreover, suppressing KIF4A expression can inhibit glioma progression. We also discovered that WZ-3146, a small molecule inhibitor of KIF4A, can induce apoptosis in glioma cells and exhibit antiglioma effects.ConclusionIn conclusion, these observations demonstrated that targeting KIF4A can inhibit glioma progression. With further research, WZ-3146, a small molecule inhibitor of KIF4A, could be combined with other molecular targeted drugs to cooperatively inhibit glioma progression.

LGG-16. BRAFV600K LOW-GRADE GLIOMA EMERGENCE DURING THERAPY FOR BRAFV600E HIGH-GRADE GLIOMA

Abstract BACKGROUND BRAFV600E mutations are prevalent in pediatric brain tumors, constituting 20% of low-grade and 5% of high-grade gliomas. Other single-nucleotide substitutions in BRAF are described in adult cancers but rarely in pediatric brain tumors. Our case sheds light on a unique scenario—a patient with a BRAF-mutated high-grade spinal glioma who later developed slowly progressive intracranial low-grade glioma, subsequently undergoing rapid high-grade transformation. METHODS Case Report RESULTS Our patient initially presented as a thirteen-year-old male with a two-month history of progressive bilateral hand weakness/paresthesias. Spine MRI revealed a fusiform expansile intramedullary neoplasm from C3-T2, brain MRI was negative. Biopsy showed an anaplastic astrocytoma with BRAFV600E mutation and MYC-N amplification. Initial treatment included proton radiation and a 2-year course of Dabrafenib/Trametinib, maintaining disease stability. After four months off therapy, he developed local progression, and re-staging brain MRI showed new cerebellar/supratentorial lesions. Dabrafenib/Trametinib was re-started until progression two years later. He developed hydrocephalus and underwent ETV and brain tumor biopsy, which revealed a low-grade glioma with BRAFV600K mutation. At this point, Dabrafenib/Trametinib continued for another 1.5 years; he exhibited slow progression of the brain tumors before a cerebellar lesion developed rapid progression. He had GTR of the rapid-growing lesion, and pathology reported a Grade 4 invasive astrocytoma harboring BRAFV600E, two VUS MTOR mutations, and MGMT promoter methylation. Current treatment involves radiation therapy concurrent with temozolomide. CONCLUSIONS While combinatorial Dabrafenib/Trametinib is effective in glioma therapy, resistance and progression challenges persist. Our case presents a unique manifestation—a patient with a spinal high-grade glioma with BRAFV600E who developed a secondary low-grade glioma with BRAFV600K in the brain, which, after several years, transformed into a high-grade glioma. Future research is crucial for comprehending the intricate role of BRAF mutations in pediatric gliomas, paving the way for improved patient outcomes.

NFS-19. ATYPICAL PRESENTATION OF GLIOMAS IN ADOLESCENTS WITH NEUROFIBROMATOSIS TYPE 1 (NF1): A CASE SERIES

Abstract BACKGROUND Patients with NF1 are at risk for developing gliomas, usually low-grade in childhood but may be high-grade in adults. In children, the most common sites of disease are the optic pathway and brainstem; tumors in these regions often arise in young children and display histological features characteristic of pilocytic astrocytoma (PA) when biopsied. Typical MRI findings include T2 hyperintense, T1 hypointense lesions with minimal contrast enhancement and no diffusion restriction. Due to the well-established pattern of low-grade tumor formation in children with NF1, as well as the surgically challenging areas in which these tumors develop, low-grade glioma (LGG) therapy is often initiated without histologic confirmation of the diagnosis in classic cases. In cases with atypical disease location, older age at presentation or imaging appearance, a biopsy may be considered to exclude higher-grade lesions. METHODS Retrospective chart review, case series RESULTS Four adolescent patients with NF1 presented with atypical suspected gliomas. All four patients underwent surgical biopsy/resection. Case 1 was a left temporal lesion in the previous radiation field for optic pathway glioma; biopsy confirmed LGG with MAP2K1 mutation and increased focal proliferation index (28%), but methylation did not match with any established classification. The patient progressed through multiple rounds of therapy and succumbed to her tumor. Case 2 was a left occipital lesion; biopsy confirmed PA with CDKN2A deletion. The tumor displayed rapid regrowth, but subsequently stabilized. Case 3 was a right frontal lesion; confirmed PA. The tumor demonstrated some regrowth but then stabilized. Case 4 was a basal ganglia lesion; confirmed PA. The patient has demonstrated stable MRI findings and has not required further intervention. CONCLUSIONS Biopsy yielded helpful prognostic information (additional mutations, proliferation rate) in half of these atypical cases. Biopsy should be carefully considered for NF1 patients with atypical presentation or a history of radiation.

Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis

Glioma is the most common malignant tumor of the central nervous system, with EZH2 playing a crucial regulatory role. This study further explores the abnormal expression of EZH2 and its mechanisms in regulating glioma progression. Additionally, it was found that IHMT-337 can potentially be a therapeutic agent for glioma. The prognosis, expression, and localization of EZH2 were determined using bioinformatics, IHC staining, Western blot (WB) analysis, and immunofluorescence (IF) localization. The effects of EZH2 on cell function were assessed using CCK-8 assays, Transwell assays, and wound healing assays. Public databases and RT-qPCR were utilized to identify downstream targets. The mechanisms regulating these downstream targets were elucidated using MS-PCR and WB analysis. The efficacy of IHMT-337 was demonstrated through IC50 measurements, WB analysis, and RT-qPCR. The effects of IHMT-337 on glioma cells in vitro were evaluated using Transwell assays, EdU incorporation assays, and flow cytometry. The potential of IHMT-337 as a treatment for glioma was assessed using a blood–brain barrier (BBB) model and an orthotopic glioma model. Our research confirms significantly elevated EZH2 expression in gliomas, correlating with patient prognosis. EZH2 facilitates glioma proliferation, migration, and invasion alongside promoting SLC12A5 DNA methylation. By regulating SLC12A5 expression, EZH2 activates the WNK1-OSR1-NKCC1 pathway, enhancing its interaction with ERM to promote glioma migration. IHMT-337 targets EZH2 in vitro to inhibit WNK1 activation, thereby suppressing glioma cell migration. Additionally, it inhibits cell proliferation and arrests the cell cycle. IHMT-337 has the potential to cross the BBB and has successfully inhibited glioma progression in vivo. This study expands our understanding of the EZH2-SLC12A5 axis in gliomas, laying a new foundation for the clinical translation of IHMT-337 and offering new insights for precision glioma therapy.

Phase II study of vemurafenib in children and young adults with tumors harboring BRAF V600 mutations: NCI-COG pediatric MATCH trial (APEC1621) Arm G.

This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (n = 7) and prior BRAF inhibitor therapy (n = 7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).

Neural Progenitor Cell-Mediated Magnetic Nanoparticles for Magnetic Resonance Imaging and Photothermal Therapy of Glioma.

Glioma is the most common primary malignant tumor in the brain. The diagnostic accuracy and treatment efficiency of glioma are facing great challenges due to the presence of the blood-brain barrier (BBB) and the high infiltration of glioma. There is an urgent need to explore the combination of diagnostic and therapeutic approaches to achieve a more accurate diagnosis, as well as guidance before and after surgery. In this work, we induced human induction of pluripotent stem cell into neural progenitor cells (NPCs) and synthesized nanoprobes labeled with enhanced green fluorescent protein (EGFP, abbreviated as MFe3O4-labeled EGFP-NPCs) for photothermal therapy. Nanoprobes carried by NPCs can effectively penetrate the BBB and target glioma for the purpose of magnetic resonance imaging and guiding surgery. More importantly, MFe3O4-labeled EGFP-NPCs can effectively induce local photothermal therapy, conduct preoperative tumor therapy, and inhibit the recurrence of postoperative glioma. This work shows that MFe3O4-labeled EGFP-NPCs is a promising nanoplatform for glioma diagnosis, accurate imaging-guided surgery, and effective photothermal therapy.

Comparative analysis of non-invasive and invasive alternating electric fields therapy for malignant gliomas: a simulation study

Alternating electric fields (AEFs) at intermediate frequencies (100–300 kHz) and low intensities (1–3 V/cm) have shown promise as an effective approach for inhibiting cancer cell proliferation. However, a noticeable research gap exists in comparing the biophysical properties of invasive and non-invasive AEFs methods, and AEFs delivery strategies require further improvement. In this study, we constructed a realistic head model to simulate the effects of non-invasive and invasive AEFs on malignant gliomas. Additionally, a novel method was proposed involving the placement of a return electrode under the scalp. We simulated the electric field and temperature distributions in the brain tissue for each method. Our results underscore the advantages of invasive AEFs, showcasing their superior tumor-targeting abilities and reduced energy requirements. The analysis of brain tissue temperature changes reveals that non-invasive AEFs primarily generate heat at the scalp level, whereas invasive methods localize heat production within the tumor itself, thereby preserving surrounding healthy brain tissue. Our proposed invasive AEFs method also shows potential for selective electric field intervention. In conclusion, invasive AEFs demonstrate potential for precise and effective tumor treatment. Its enhanced targeting capabilities and limited impact on healthy tissue make it a promising avenue for further research in the realm of cancer treatment.

Isocitrate Dehydrogenase Inhibitors in Glioma: From Bench to Bedside.

Isocitrate dehydrogenase (IDH) mutant gliomas are a primary malignancy of the central nervous system (CNS) malignancies, most commonly affecting adults under the age of 55. Standard of care therapy for IDH-mutant gliomas involves maximal safe resection, radiotherapy, and chemotherapy. However, despite good initial responses to multimodality treatment, recurrence is virtually universal. IDH-mutant gliomas represent a life-limiting prognosis. For this reason, there is a great need for novel treatments that can prolong survival. Uniquely for IDH-mutant gliomas, the IDH mutation is the direct driver of oncogenesis through its oncometabolite 2-hydroxygluterate. Inhibition of this mutated IDH with a corresponding reduction in 2-hydroxygluterate offers an attractive treatment target. Researchers have tested several IDH inhibitors in glioma through preclinical and early clinical trials. A phase III clinical trial of an IDH1 and IDH2 inhibitor vorasidenib yielded promising results among patients with low-grade IDH-mutant gliomas who had undergone initial surgery and no radiation or chemotherapy. However, many questions remain regarding optimal use of IDH inhibitors in clinical practice. In this review, we discuss the importance of IDH mutations in oncogenesis of adult-type diffuse gliomas and current evidence supporting the use of IDH inhibitors as therapeutic agents for glioma treatment. We also examine unresolved questions and propose potential directions for future research.

Antisense Oligonucleotides for Rapid Translation of Gene Therapy in Glioblastoma

Purpose: The limited efficacy of current treatments for malignant brain tumors necessitates novel therapeutic strategies. This study aimed to assess the potential of antisense oligonucleotides (ASOs) as adjuvant therapy for high-grade gliomas, focusing on their CNS penetration and clinical translation prospects. Methods: A comprehensive review of the existing literature was conducted to evaluate the implications of ASOs in neuro-oncology. Studies that investigated ASO therapy’s efficacy, CNS penetration, and safety profile were analyzed to assess its potential as a therapeutic intervention for high-grade gliomas. Results: ASOs present a promising avenue for enhancing targeted gene therapies in malignant gliomas. Their potent CNS penetration, in vivo durability, and efficient transduction offer advantages over conventional treatments. Preliminary in vivo and in vitro studies suggest ASOs as a viable adjuvant therapy for high-grade gliomas, warranting further exploration in clinical trials. Conclusions: ASOs hold significant promise as adjuvant therapy for high-grade gliomas, offering improved CNS penetration and durability compared with existing treatments. While preliminary studies are encouraging, additional research is needed to establish the safety and efficacy of ASO therapy in clinical settings. Further investigation and clinical trials are warranted to validate ASOs as a transformative approach in neuro-oncology.

Biomimetic Dual-Target Theranostic Nanovaccine Enables Magnetic Resonance Imaging and Chemo/Chemodynamic/Immune Therapy of Glioma.

Development of theranostic nanomedicines to tackle glioma remains to be challenging. Here, we present an advanced blood-brain barrier (BBB)-crossing nanovaccine based on cancer cell membrane-camouflaged poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) incorporated with MnO2 and doxorubicin (DOX). We show that the disulfide bond-cross-linked redox-responsive PVCL NGs can be functionalized with dermorphin and imiquimod R837 through cell membrane functionalization. The formed functionalized PVCL NGs having a size of 220 nm are stable, can deplete glutathione, and responsively release both Mn2+ and DOX under the simulated tumor microenvironment to exert the chemo/chemodynamic therapy mediated by DOX and Mn2+, respectively. The combined therapy induces tumor immunogenic cell death to maturate dendritic cells (DCs) and activate tumor-killing T cells. Further, the nanovaccine composed of cancer cell membranes as tumor antigens, R837 as an adjuvant with abilities of DC maturation and macrophages M1 repolarization, and MnO2 with Mn2+-mediated stimulator of interferon gene activation of tumor cells can effectively act on both targets of tumor cells and immune cells. With the dermorphin-mediated BBB crossing, cell membrane-mediated homologous tumor targeting, and Mn2+-facilitated magnetic resonance (MR) imaging property, the designed NG-based theranostic nanovaccine enables MR imaging and combination chemo-, chemodynamic-, and imnune therapy of orthotopic glioma with a significantly decreased recurrence rate.

Prolonged response to entrectinib in an adult patient with recurrent glioblastoma harboring a GOPC::ROS1 fusion

Introductory paragraph Data on the use of targeted therapies in glioma are still limited and the identification of useful targetable mutations is still under investigation. Among all the relevant alterations identified through next generation sequencing (NGS) tests, ROS1 alterations can rarely be found in gliomas, and the most common of them is GOPC::ROS1 fusion. Targeted therapies, such as entrectinib, are available for such alterations. Hereby, the case of a patient affected by GOPC::ROS1 fused glioblastoma and treated with entrectinib is presented; this patient achieved a complete and prolonged response with no relevant toxicities from the treatment.

Fractionated radiation therapy alters energy metabolism and induces cellular quiescence exit in patient-derived orthotopic xenograft models of high-grade glioma

Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), of which the prognosis remains poor. To gain an in-depth understanding of biological consequences beyond the classic DNA damage, we treated 9 patient-derived orthotopic xenograft (PDOX) models, including one with DNA mismatch repair (MMR) deficiency, with fractionated radiations (2 Gy/day x 5 days). Extension of survival time was noted in 5 PDOX models (P < 0.05) accompanied by γH2AX positivity in >95 % tumor cells in tumor core and >85 % in the invasive foci as well as ∼30 % apoptotic and mitotic catastrophic cell death. The model with DNA MMR (IC-1406HGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. Altered metabolism, including mitochondria number elevation, COX IV activation and reactive oxygen species accumulation, were detected together with the enrichment of CD133+ tumor cells. The latter was caused by the entry of quiescent G0 cells into cell cycle and the activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes. These novel insights about the cellular and molecular mechanisms of fractionated radiation in vivo should support the development of new radio-sensitizing therapies.

Laminin-associated integrins mediate Diffuse Intrinsic Pontine Glioma infiltration and therapy response within a neural assembloid model

Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive and fatal pediatric brain cancer. One pre-requisite for tumor cells to infiltrate is adhesion to extracellular matrix (ECM) components. However, it remains largely unknown which ECM proteins are critical in enabling DIPG adhesion and migration and which integrin receptors mediate these processes. Here, we identify laminin as a key ECM protein that supports robust DIPG cell adhesion and migration. To study DIPG infiltration, we developed a DIPG-neural assembloid model, which is composed of a DIPG spheroid fused to a human induced pluripotent stem cell-derived neural organoid. Using this assembloid model, we demonstrate that knockdown of laminin-associated integrins significantly impedes DIPG infiltration. Moreover, laminin-associated integrin knockdown improves DIPG response to radiation and HDAC inhibitor treatment within the DIPG-neural assembloids. These findings reveal the critical role of laminin-associated integrins in mediating DIPG progression and drug response. The results also provide evidence that disrupting integrin receptors may offer a novel therapeutic strategy to enhance DIPG treatment outcomes. Finally, these results establish DIPG-neural assembloid models as a powerful tool to study DIPG disease progression and enable drug discovery.

Laser interstitial thermal therapy (LITT) for pediatric low-grade glioma—case presentations and lessons learned

BackgroundThe surgical treatment of brain tumors has developed over time, offering customized strategies for patients and their specific lesions. One of the most recent advances in pediatric neuro-oncological surgery is laser interstitial thermal therapy (LITT). However, its effectiveness and indications are still being evaluated. The aim of this work is to review the current literature on LITT for pediatric low-grade gliomas (pLGG) and evaluate our initial results in this context.MethodsWe retrospectively reviewed our pediatric neurosurgery database for patients who received LITT treatment between November 2019 and December 2023. We collected data on the indications for LITT, technical issues during the procedure, and clinical and radiological follow-up.ResultsThree patients underwent 5 LITT procedures for pLGG. The lesion was thalamo-peduncular in one patient, cingulate in one, and deep parietal in one patient. Two patients had a previous open resection done and were diagnosed with pLGG. One patient underwent a stereotaxic biopsy during the LITT procedure that was non-diagnostic. The same patient underwent a later open resection of the tumor in the cingulate gyrus. There were no surgical complications and all patients were discharged home on the first post-operative day. The follow-up period was between 20 and 40 months. Radiological follow-up showed a progressive reduction of the tumor in patients with LGG.ConclusionLaser interstitial thermal therapy is a minimally invasive treatment that shows promise in treating deep-seated pLGG in children. The treatment has demonstrated a reduction in tumor volume, and the positive results continue over time. LITT can be used as an alternative treatment for tumors located in areas that are difficult to access surgically or in cases where other standard treatment options have failed.