Glioma Therapy Research Articles

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.

Clinical analysis of the efficacy of radiation therapy for primary high-grade gliomas guided by biological rhythms

ObjectiveHigh-grade glioma (HGG) patients frequently encounter treatment resistance and relapse, despite numerous interventions seeking enhanced survival outcomes yielding limited success. Consequently, this study, rooted in our prior research, aimed to ascertain whether leveraging circadian rhythm phase attributes could optimize radiotherapy results. MethodsIn this retrospective analysis, we meticulously selected 121 HGG cases with synchronized rhythms through Cosinor analysis. Post-surgery, all subjects underwent standard radiotherapy alongside Temozolomide chemotherapy. Random allocation ensued, dividing patients into morning (N = 69) and afternoon (N = 52) radiotherapy cohorts, enabling a comparison of survival and toxicity disparities. ResultsThe afternoon radiotherapy group exhibited improved overall survival (OS) and progression-free survival (PFS) relative to the morning cohort. Notably, median OS extended to 25.6 months versus 18.5 months, with P = 0.014, with median PFS at 20.6 months versus 13.3 months, with P = 0.022, post-standardized radiotherapy. Additionally, lymphocyte expression levels in the afternoon radiation group 32.90(26.10, 39.10) significantly exceeded those in the morning group 31.30(26.50, 39.20), with P = 0.032. ConclusionsThis study underscores the markedly prolonged average survival within the afternoon radiotherapy group. Moreover, lymphocyte proportion demonstrated a notable elevation in the afternoon group. Timely and strategic adjustments of therapeutic interventions show the potential to improve therapeutic efficacy, while maintaining vigilant systemic immune surveillance. A comprehensive grasp of physiological rhythms governing both the human body and tumor microenvironment can refine treatment efficacy, concurrently curtailing immune-related damage—a crucial facet of precision medicine.

Engineered Cell Membrane-Coated Nanoparticles: New Strategies in Glioma Targeted Therapy and Immune Modulation.

Gliomas, the most prevalent primary brain tumors, pose considerable challenges due to their heterogeneity, intricate tumor microenvironment (TME), and blood-brain barrier (BBB), which restrict the effectiveness of traditional treatments like surgery and chemotherapy. This review provides an overview of engineered cell membrane technologies in glioma therapy, with a specific emphasis on targeted drug delivery and modulation of the immune microenvironment. This study investigates the progress in engineered cell membranes, encompassing physical, chemical, and genetic alterations, to improve drug delivery across the BBB and effectively target gliomas. The examination focuses on the interaction of engineered cell membrane-coated nanoparticles (ECM-NPs) with the TME in gliomas, emphasizing their potential to modulate glioma cell behavior and TME to enhance therapeutic efficacy. The review further explores the involvement of ECM-NPs in immunomodulation techniques, highlighting their impact on immune reactions. While facing obstacles related to membrane stability and manufacturing scalability, the review outlines forthcoming research directions focused on enhancing membrane performance. This review underscores the promise of ECM-NPs in surpassing conventional therapeutic constraints, proposing novel approaches for efficacious glioma treatment.

Efficacy of Operative Ultrasonography Plus Neuronavigation for Brain Glioma Surgery: 2 – Year Single Center Experience in a Developing Country

Background: preoperative MRI data has been the gold standard for the diagnosis and therapy of malignant gliomas for decades, and operative ultrasonography for the management of patients with neurological pathologies that require surgical treatment has been also used for many years as it provides additional image guidance for surgical procedure to neuronavigation techniques. The main objective of this study is to find out if the use of operative ultrasonography in glioma surgery could give greater benefit in the total resection of brain gliomas and how improvement influences the degree of neoplastic resection on the survival of patients. Methods: prospective case-control study that was performed at the ISSEMyM Licenciado Arturo Montiel Rojas Medical Center, of patients with a histopathological diagnosis of cerebral glioma treated by the neurosurgery service in the period between January 2018 and December 2020. Results: Thirty - two patients were included, with 13 patients (40.6%) with grade IV astrocytoma. Operative USG + NNV was used in 17 patients and a subtotal or total resection was achieved in 75% of the patients, with a significantly lower postoperative volumetry in patients operated on by NNV + USG (5.6mm3 + 2.5), compared to NNV alone (8mm3 + 2.8) However, these results did not affect tumor-free time, which was comparable between both groups. Conclusions: Surgical treatment of brain gliomas with USG + NNV has a good degree of tumor resection compared to those treated with NNV only, but the main factor affecting survival is the hystophatological grade of the tumor.

Advances in Targeted Glioma Therapy with Transferrin-Conjugated Gemcitabine-Loaded PLGA Nanoparticles

Advances in Targeted Glioma Therapy with Transferrin-Conjugated Gemcitabine-Loaded PLGA Nanoparticles

Crosstalk of different cell-death patterns predicts prognosis and drug sensitivity in glioma

BackgroundGlioma is a malignant brain tumor originating from glial cells, and there still a challenge to accurately predict the prognosis. Programmed cell death (PCD) plays a key role in tumorigenesis and immune response. However, the crosstalk and potential role of various PCDs in prognosis and tumor microenvironment remains unknown. Therefore, we comprehensively discussed the relationship between different models of PCD and the prognosis of glioma and provided new ideas for the optimal targeted therapy of glioma. Materials and methodsWe compared and analyzed the role of 14 PCD patterns on the prognosis from different levels. We constructed the cell death risk score (CDRS) index and conducted a comprehensive analysis of CDRS and TME characteristics, clinical characteristics, and drug response. ResultsEffects of different PCDs at the genomic, functional, and immune microenvironment levels were discussed. CDRS index containing 6 gene signatures and a nomogram were established. High CDRS is associated with a worse prognosis. Through transcriptome and single-cell data, we found that patients with high CDRS showed stronger immunosuppressive characteristics. Moreover, the high-CDRS group was resistant to the traditional glioma chemotherapy drug Vincristine, but more sensitive to the Temozolomide and the clinical experimental drug Bortezomib. In addition, we identified 19 key potential therapeutic targets during malignant differentiation of tumor cells. ConclusionOverall, we provide the first systematic description of the role of 14 PCDs in glioma. A new CDRS model was built to predict the prognosis and to provide a new idea for the targeted therapy of glioma.

Ensemble learning prediction framework for EGFR amplification status of glioma based on terahertz spectral features

Epidermal growth factor receptor (EGFR) plays a pivotal role in the initiation and progression of gliomas. In particular, in glioblastoma, EGFR amplification emerges as a catalyst for invasion, proliferation, and resistance to radiotherapy and chemotherapy. Current approaches are not capable of providing rapid diagnostic results of molecular pathology. In this study, we propose a terahertz spectroscopic approach for predicting the EGFR amplification status of gliomas for the first time. A machine learning model was constructed using the terahertz response of the measured glioma tissues, including the absorption coefficient, refractive index, and dielectric loss tangent. The novelty of our model is the integration of three classical base classifiers, i.e., support vector machine, random forest, and extreme gradient boosting. The ensemble learning method combines the advantages of various base classifiers, this model has more generalization ability. The effectiveness of the proposed method was validated by applying an individual test set. The optimal performance of the integrated algorithm was verified with an area under the curve (AUC) maximum of 85.8 %. This signifies a significant stride toward more effective and rapid diagnostic tools for guiding postoperative therapy in gliomas.

Enhancing glioma-specific drug delivery through self-assembly of macrophage membrane and targeted polymer assisted by low-frequency ultrasound irradiation

The blood-brain Barrier (BBB), combined with immune clearance, contributes to the low efficacy of drug delivery and suboptimal treatment outcomes in glioma. Here, we propose a novel approach that combines the self-assembly of mouse bone marrow-derived macrophage membrane with a targeted positive charge polymer (An-PEI), along with low-frequency ultrasound (LFU) irradiation, to achieve efficient and safe therapy for glioma. Our findings demonstrate the efficacy of a charge-induced self-assembly strategy, resulting in a stable co-delivery nanosystem with a high drug loading efficiency of 44.2 %. Moreover, this structure triggers a significant release of temozolomide in the acidic environment of the tumor microenvironment. Additionally, the macrophage membrane coating expresses Spyproteins, which increase the amount of An-BMP-TMZ that can evade the immune system by 40 %, while LFU irradiation treatment facilitates the opening of the BBB, allowing for enormously increased entry of An-BMP-TMZ (approximately 400 %) into the brain. Furthermore, after crossing the BBB, the Angiopep-2 peptide-modified An-BMP-TMZ exhibits the ability to selectively target glioma cells. These advantages result in an obvious tumor inhibition effect in animal experiments and significantly improve the survival of glioma-bearing mice. These results suggest that combining the macrophage membrane-coated drug delivery system with LFU irradiation offers a feasible approach for the accurate, efficient and safe treatment of brain disease.

Biomimetic Nanocomposites for Glioma Imaging and Therapy.

Glioma, the most common primary brain tumor, is highly invasive and grows rapidly. As such, the survival of glioma patients is relatively short, highlighting the vital importance of timely diagnosis and treatment of glioma. However, the blood brain barrier (BBB) and the non-targeting delivery systems of contrast agents and drugs greatly hinder the effective glioma imaging and therapy. Fortunately, in recent years, investigators have constructed various biomimetic delivery platforms utilizing the exceptional advantages of biomimetic nanocomposites, such as immune evasion, homologous targeting ability, and BBB penetrating ability, to achieve efficient and precise delivery of substances to glioma sites for improved diagnosis and treatment. In this concept, we present the application of these biomimetic nanocomposites in fluorescence imaging (FI), magnetic resonance imaging (MRI), and multi-modal imaging, as well as in chemotherapy, phototherapy, and combined therapy for glioma. Lastly, we provide our perspective on this research field.

Mesenchymal stem cells as therapeutic vehicles for glioma.

Glioma is a disease with a poor prognosis despite the availability of multimodality treatments, and the development of novel therapies is urgently needed. Challenges in glioma treatment include the difficulty for drugs to cross the blood-brain barrier when administered systemically and poor drug diffusion when administered locally. Mesenchymal stem cells exhibit advantages for glioma therapy because of their ability to pass through the blood-brain barrier and migrate to tumor cells and their tolerance to the immune system. Therefore, mesenchymal stem cells have been explored as vehicles for various therapeutic agents for glioma treatment. Mesenchymal stem cells loaded with chemotherapeutic drugs show improved penetration and tumor accumulation. For gene therapy, mesenchymal stem cells can be used as vehicles for suicide genes, the so-called gene-directed enzyme prodrug therapy. Mesenchymal stem cell-based oncolytic viral therapies have been attempted in recent years to enhance the efficacy of infection against the tumor, viral replication, and distribution of viral particles. Many uncertainties remain regarding the function and behavior of mesenchymal stem cells in gliomas. However, strategies to increase mesenchymal stem cell migration to gliomas may improve the delivery of therapeutic agents and enhance their anti-tumor effects, representing promising potential for patient treatment.

2-Hydroxyglutarate as an MR spectroscopic predictor of an IDH mutation in gliomas.

The mutated enzyme isocitrate dehydrogenase (IDH) 1 and 2 has been detected in various tumor entities such as gliomas and can convert α-ketoglutarate into the oncometabolite 2-hydroxyglutarate (2-HG). This neuro-oncologically significant metabolic product can be detected by MR spectroscopy and is therefore suitable for noninvasive glioma classification and therapy monitoring.This paper provides an up-to-date overview of the methodology and relevance of 1H-MR spectroscopy (MRS) in the oncological primary and follow-up diagnosis of gliomas. The possibilities and limitations of this MR spectroscopic examination are evaluated on the basis of the available literature.By detecting 2-HG, MRS can in principle offer a noninvasive alternative to immunohistological analysis thus avoiding surgical intervention in some cases. However, in addition to an adapted and optimized examination protocol, the individual measurement conditions in the examination region are of decisive importance. Due to the inherently small signal of 2-HG, unfavorable measurement conditions can influence the reliability of detection. · MR spectroscopy enables the non-invasive detection of 2-hydroxyglutarate.. · The measurement of this metabolite allows the detection of an IDH mutation in gliomas.. · The choice of MR examination method is particularly important.. · Detection reliability is influenced by glioma size, necrotic tissue and the existing measurement conditions.. · Bauer J, Raum HN, Kugel H et al. 2-Hydroxyglutarate as an MR spectroscopic predictor of an IDH mutation in gliomas. Fortschr Röntgenstr 2024; DOI 10.1055/a-2285-4923.

Efficacy of interstitial photodynamic therapy using talaporfin sodium and a semiconductor laser for a mouse allograft glioma model

To investigate the therapeutic potential of photodynamic therapy (PDT) for malignant gliomas arising in unresectable sites, we investigated the effect of tumor tissue damage by interstitial PDT (i-PDT) using talaporfin sodium (TPS) in a mouse glioma model in which C6 glioma cells were implanted subcutaneously. A kinetic study of TPS demonstrated that a dose of 10 mg/kg and 90 min after administration was appropriate dose and timing for i-PDT. Performing i-PDT using a small-diameter plastic optical fiber demonstrated that an irradiation energy density of 100 J/cm2 or higher was required to achieve therapeutic effects over the entire tumor tissue. The tissue damage induced apoptosis in the area close to the light source, whereas vascular effects, such as fibrin thrombus formation occurred in the area slightly distant from the light source. Furthermore, when irradiating at the same energy density, irradiation at a lower power density for a longer period of time was more effective than irradiation at a higher power density for a shorter time. When performing i-PDT, it is important to consider the rate of delivery of the irradiation light into the tumor tissue and to set irradiation conditions that achieve an optimal balance between cytotoxic and vascular effects.

Translational research of boron neutron capture therapy for spinal cord gliomas using rat model

Boron neutron capture therapy (BNCT) is a type of targeted particle radiation therapy with potential applications at the cellular level. Spinal cord gliomas (SCGs) present a substantial challenge owing to their poor prognosis and the lack of effective postoperative treatments. This study evaluated the efficacy of BNCT in a rat SCGs model employing the Basso, Beattie, and Bresnahan (BBB) scale to assess postoperative locomotor activity. We confirmed the presence of adequate in vitro boron concentrations in F98 rat glioma and 9L rat gliosarcoma cells exposed to boronophenylalanine (BPA) and in vivo tumor boron concentration 2.5 h after intravenous BPA administration. In vivo neutron irradiation significantly enhanced survival in the BNCT group when compared with that in the untreated group, with a minimal BBB scale reduction in all sham-operated groups. These findings highlight the potential of BNCT as a promising treatment option for SCGs.