Search Results (39)

Glioblastoma (GBM) is an aggressive and highly heterogeneous tumor that frequently recurs despite surgery followed by radio-chemotherapy and, more recently, TTFields. This recurrence is largely driven by glioblastoma stem cells (GSCs), which are intrinsically resistant to standard therapies. Identifying molecular targets that underlie this resistance is therefore critical. Here, we investigated whether the inhibition of FGFR1, previously identified as a key mediator of GBM radioresistance, using pemigatinib, a selective FGFR1–3 inhibitor, could enhance GSC radiosensitivity in vitro and in vivo. Pemigatinib treatment inhibited FGFR1 signaling, promoted proteasome-dependent FGFR1 degradation, and reduced the viability, neurosphere formation, and sphere size in GSCs with unmethylated MGMT, a subgroup known for poor response to standard treatments. In MGMT-unmethylated differentiated GBM cell lines, pemigatinib combined with temozolomide further enhanced radiosensitivity. Transcriptomic analysis revealed that pemigatinib treatment led to the downregulation of S100A4, a biomarker associated with mesenchymal transition, angiogenesis, and immune modulation in GBM. Functional studies confirmed that silencing S100A4 significantly improved GSCs’ response to irradiation. In vivo, pemigatinib combined with localized irradiation produced the longest median survival compared to either treatment alone in mice bearing orthotopic GSC-derived tumors, although the difference was not statistically significant. These findings support further clinical investigation to validate these preclinical findings and determine the potential role of FGFR inhibition as part of multimodal GBM therapy. Full article

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, has a poor prognosis due to rapid recurrence and treatment resistance. This review examines the evolution of radiotherapy (RT) for GBM management, from whole-brain RT to modern techniques like intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), guided by 2023 European Society for Radiotherapy and Oncology (ESTRO)-European Association of Neuro-Oncology (EANO) and 2025 American Society for Radiation Oncology (ASTRO) recommendations. The standard Stupp protocol (60 Gy/30 fractions with temozolomide [TMZ]) improves overall survival (OS) to 14.6 months, with greater benefits in O6-methylguanine-DNA methyltransferase (MGMT)-methylated tumors (21.7 months). Tumor Treating Fields (TTFields) extend median overall survival (mOS) to 31.6 months in MGMT-methylated patients and 20.9 months overall in supratentorial GBM (EF-14 trial). However, 80–90% of recurrences occur within 2 cm of the irradiated field due to tumor infiltration and radioresistance driven by epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) mutations, cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions, tumor hypoxia, and tumor stem cells. Pseudoprogression, distinguished using Response Assessment in Neuro-Oncology (RANO) criteria and positron emission tomography (PET), complicates response evaluation. Targeted therapies (e.g., bevacizumab; PARP inhibitors) and immunotherapies (e.g., pembrolizumab; oncolytic viruses), alongside advanced imaging (multiparametric magnetic resonance imaging [MRI], amino acid PET), support personalized RT. Ongoing trials evaluating reirradiation, hypofractionation, stereotactic radiosurgery, neoadjuvant therapies, proton therapy (PT), boron neutron capture therapy (BNCT), and AI-driven planning aim to enhance efficacy for GBM IDH-wildtype, but phase III trials are needed to improve survival and quality of life. Full article

Tumor-Treating Fields (TTFields), a novel therapeutic avenue, is approved for therapy in Glioblastoma multiforme, malignant pleural mesothelioma, and metastatic non-small cell lung cancer (NSCLC). In pancreatic ductal adenocarcinoma (PDAC), several clinical trials are underway to improve outcomes, yet a significant knowledge gap prevails involving the cell-extracellular matrix (ECM) crosstalk. Herein, we hypothesized that treatment with TTFields influence this crosstalk, which is reflected by the dynamic alteration in nanomechanical properties (NMPs) of cells and the ECM in a co-culture system. We employed an ECM gel comprising collagen, fibronectin, and laminin mixed in 100:1:1 stoichiometry to co-culture of Panc1 and AsPC1 individually. This ECM mixture mimics the in vivo tumor microenvironment closely when compared to the individual ECM components studied before. A comprehensive frequency-dependent study revealed the optimal TTFields frequency to be 150 kHz. We also observed that irrespective of the ECM’s presence, TTFields increase cell membrane stiffness and decrease deformation several-folds in both Panc1 and AsPC1 cells at both 48 h and 72 h. Although adhesion for AsPC1 decreased at 48 h, at 72 h it was observed to increase irrespective of ECM’s presence. Moreover, it significantly alters the NMPs of ECM gels when co-cultured with PDAC cell lines. However, AsPC1 cells were observed to be more detrimental to these changes. Lastly, we attribute the stiffness changes in Panc1 cells to the membrane F-actin reorganization in the presence of TTFields. This study paves a path to study complex PDAC TME as well as the effect of various chemotherapeutic agents on such TME with TTFields in the future. Full article

Glioblastoma (GBM) remains a challenging cancer to treat with limited effective therapies. Standard treatments, including surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy, offer marginal survival benefits but are often limited by side effects and drug resistance. Temozolomide is the most commonly used chemotherapy; however, resistance and lack of efficacy in recurrent GBM hinder its success. Tumor treating fields (TTFields), a novel non-invasive modality that utilizes alternating electric fields, have recently emerged as a promising treatment for GBM. TTFields work by disrupting the function of the mitotic spindle and inducing apoptosis in cancer cells. They can be especially effective when combined with other therapies. TTFields enhance drug delivery when paired with chemotherapy by increasing the permeability of the blood–brain barrier and cell membranes, leading to more effective tumor inhibition. Similarly, TTFields increase cancer cell sensitivity to radiation therapy and improve the efficacy of targeted therapies, such as sorafenib and immunotherapy, particularly in extra-cranial tumors. The Optune device, the primary medical device for TTFields’ delivery, offers a convenient and versatile treatment option, allowing remote care and exhibiting fewer adverse effects. This review discusses the potential of TTFields as a valuable addition to GBM treatment, particularly in combination therapies, and highlights the device’s clinical applications. Full article

Pediatric primary brain tumors pose significant therapeutic challenges due to their aggressive nature and the critical environment of the developing brain. Traditional modalities like surgery, chemotherapy, and radiotherapy often achieve limited success in high-grade gliomas and embryonal tumors. Tumor-treating fields (TTfields), a non-invasive therapy delivering alternating electric fields, has emerged as a promising approach to disrupt tumor cell division through mechanisms such as mitotic disruption, DNA damage, and tumor microenvironment modulation. TTfields are thought to selectively target dividing tumor cells while sparing healthy, non-dividing cells. While TTfields therapy is FDA-approved for the management of glioblastoma and other cancers, its application in pediatric brain tumors remains under investigation. Preclinical studies reveal its potential in medulloblastoma and ependymoma models, while observational data suggest its safety and feasibility in children. Current research focuses on optimizing TTfields’ efficacy through advanced technologies, including high-intensity arrays, skull remodeling, and integration with immunotherapies such as immune checkpoint inhibitors. Innovative device-based therapies like magnetic field-based technologies further expand the treatment possibilities. As clinical trials progress, TTfields and related modalities offer hope for addressing unmet needs in pediatric neuro-oncology, especially for tumors in challenging locations. Future directions include biomarker identification, tailored protocols, and novel therapeutic combinations to enhance outcomes in pediatric brain tumor management. Full article

Glioblastoma (GBM) is a lethal primary brain cancer with a 5.6% five-year survival rate. Tumor treating fields (TTFields) are alternating low-intensity electric fields that have demonstrated a GBM patient survival benefit. We previously reported that 0.5–24 h of TTFields exposure resulted in an increased uptake of FITC-dextran fluorescent probes (4–20 kDa) in human GBM cells. However, this approach, in which a fluorescence plate-based detector is used to evaluate cells attached to glass coverslips, cannot distinguish FITC-dextran uptake in live vs. dead cells. The goal of the study was to report the optimization and validation of two independent methods to quantify human GBM cell membrane permeabilization induced by TTFields exposure. First, we optimized flow cytometry by measuring mean fluorescence intensity at 72 h for 4 kDa (TTFields 6726 ± 958.0 vs. no-TTFields 5093 ± 239.7, p = 0.016) and 20 kDa (7087 ± 1137 vs. 5055 ± 897.8, p = 0.031) probes. Second, we measured the ratio of lactate dehydrogenase (LDH) to cell viability (measured using the CellTiter-Glo [CTG] viability assay); the LDH/CTG ratio was higher under TTFields (1.47 ± 0.15) than no-TTFields (1.08 ± 0.08) conditions, p < 0.0001. The findings using these two independent methods reproducibly demonstrated their utility for time-dependent evaluations. We also showed that these methods can be used to relate the cell membrane-permeabilizing effects of the non-ionizing radiation of TTFields to that of an established cell membrane permeabilizer, the non-ionic detergent Triton-X-100. Evaluating carboplatin ± TTFields, the LDH/CTG ratio was significantly higher in the TTFields vs. no-TTFields condition at each carboplatin concentration (0–30 µM), p = 0.014. We successfully optimized and validated two cost-effective methods to reproducibly quantify TTFields-induced human GBM cancer cell membrane permeabilization. Full article

Glioblastoma, the most common and aggressive primary brain tumor in adults, presents a formidable challenge due to its rapid progression, treatment resistance, and poor survival outcomes. Standard care typically involves maximal safe surgical resection, followed by fractionated external beam radiation therapy and concurrent temozolomide chemotherapy. Despite these interventions, median survival remains approximately 12–15 months, with a five-year survival rate below 10%. Prognosis is influenced by factors such as patient age, molecular characteristics, and the extent of resection. Patients with IDH-mutant tumors or methylated MGMT promoters generally have improved survival, while recurrent glioblastoma is associated with a median survival of only six months, as therapies in these cases are often palliative. Innovative treatments, including TTFields, add incremental survival benefits, extending median survival to around 20.9 months for eligible patients. Symptom management—addressing seizures, headaches, and neurological deficits—alongside psychological support for patients and caregivers is essential to enhance quality of life. Emerging targeted therapies and immunotherapies, though still limited in efficacy, show promise as part of an evolving treatment landscape. Continued research and clinical trials remain crucial to developing more effective treatments. This multidisciplinary approach, incorporating diagnostics, personalized therapy, and supportive care, aims to improve outcomes and provides a hopeful foundation for advancing glioblastoma management. Full article

According to a modern view, cancer no longer follows a purely mechanistic model. Rather, a tumor is conceived as a more complex structure, composed of cancer cells, the activities of which may interact and reshape the so-called tumor microenvironment (TME), leading to preservation of specific tumoral niches and promoting the survival of tumoral stem cells. Background/Objective: Therapeutic strategies must deal with this unique cancer architecture in the near future by widening their range of activities outside the cancer cells and rewiring a TME to ensure it is hostile to cancer growth. Therefore, an intratumoral therapeutic strategy may open the door to a new type of anticancer activity, one that directly injures the tumoral structure while also eliciting an influence on the TME through local and systemic immunomodulation. This review would like to assess the current situation of intratumoral strategies and their clinical implications. Methods We analyzed data from phase I, II, and III trials, comprehensive reviews and relevant clinical and preclinical research, from robust databases, like PUBMED, EMBASE, Cochrane Library, and clinicaltrials.gov. Results: Intratumoral strategies can be quite variable. It is possible the injection and inhalation of traditional antiblastic agents or immunomodulant agents, or intrapleural administration. Ablation strategy is available, both thermal and photodynamic method. Moreover, TTfields and NPs are analyzed and also brachytherapy is mentioned. Intratumoral therapy can find space in “adjuvant”/perioperative or metastatic settings. Finally, intratumoral strategies allow to synergize their activities with systemic therapies, guaranteeing better local and systemic disease control. Conclusions: Intratumoral strategies are overall promising. Antiblastic/immunomodulant injection and NPs use are especially interesting and intriguing. But, there is generally a lack of phase II and III trials, in particular NPs use need additional experimentation and clinical studies. Full article

Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain tumor, characterized by a daunting prognosis with a life expectancy hovering around 12–16 months. Despite a century of relentless research, only a select few drugs have received approval for brain tumor treatment, largely due to the formidable barrier posed by the blood–brain barrier. The current standard of care involves a multifaceted approach combining surgery, irradiation, and chemotherapy. However, recurrence often occurs within months despite these interventions. The formidable challenges of drug delivery to the brain and overcoming therapeutic resistance have become focal points in the treatment of brain tumors and are deemed essential to overcoming tumor recurrence. In recent years, a promising wave of advanced treatments has emerged, offering a glimpse of hope to overcome the limitations of existing therapies. This review aims to highlight cutting-edge technologies in the current and ongoing stages of development, providing patients with valuable insights to guide their choices in brain tumor treatment. Full article

Glioblastoma is an aggressive, incurable brain cancer with poor five-year survival rates of around 13% despite multimodal treatment with surgery, DNA-damaging chemoradiotherapy and the recent addition of Tumour Treating Fields (TTFields). As such, there is an urgent need to improve our current understanding of cellular responses to TTFields using more clinically and surgically relevant models, which reflect the profound spatial heterogeneity within glioblastoma, and leverage these biological insights to inform the rational design of more effective therapeutic strategies incorporating TTFields. We have recently reported the use of preclinical TTFields using the inovitro^TM system within 2D glioma stem-like cell (GSC) models and demonstrated significant cytotoxicity enhancement when co-applied with a range of therapeutically approved and preclinical DNA damage response inhibitors (DDRi) and chemoradiotherapy. Here we report the development and optimisation of preclinical TTFields delivery within more clinically relevant 3D scaffold-based primary GSC models of spatial heterogeneity, and highlight some initial enhancement of TTFields potency with temozolomide and clinically approved PARP inhibitors (PARPi). These studies, therefore, represent an important platform for further preclinical assessment of TTFields-based therapeutic strategies within clinically relevant 3D GSC models, aimed towards accelerating clinical trial implementation and the ultimate goal of improving the persistently dire survival rates for these patients. Full article

Tumor treating fields (TTFields), a biophysical therapy technology that uses alternating electric fields to inhibit tumor proliferation, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of newly diagnosed or recurrent glioblastomas (GBM) and malignant pleural mesotheliomas (MPM). Clinical trials have confirmed that TTFields are effective in slowing the tumor growth and prolonging patient survival. In recent years, many researchers have found that TTFields can induce anti-tumor immune responses, and their main mechanisms include upregulating the infiltration ratio and function of immune cells, inducing the immunogenic cell death of tumor cells, modulating immune-related signaling pathways, and upregulating the expression of immune checkpoints. Treatment regimens combining TTFields with tumor immunotherapy are emerging as a promising therapeutic approach in clinical practice. Given the increasing number of recently published studies on this topic, we provide an updated review of the mechanisms and clinical implications of TTFields in inducing anti-tumor immune responses. This review not only has important reference value for an in-depth study of the anticancer mechanism of TTFields but also provides insights into the future clinical application of TTFields. Full article

Treatment for the deadly brain tumor glioblastoma (GBM) has been improved through the non-invasive addition of alternating electric fields, called tumor treating fields (TTFields). Improving both progression-free and overall survival, TTFields are currently approved for treatment of recurrent GBMs as a monotherapy and in the adjuvant setting alongside TMZ for newly diagnosed GBMs. These TTFields are known to inhibit mitosis, but the full molecular impact of TTFields remains undetermined. Therefore, we sought to understand the ability of TTFields to disrupt the growth patterns of and induce kinomic landscape shifts in TMZ-sensitive and -resistant GBM cells. We determined that TTFields significantly decreased the growth of TMZ-sensitive and -resistant cells. Kinomic profiling predicted kinases that were induced or repressed by TTFields, suggesting possible therapy-specific vulnerabilities. Serving as a potential pro-survival mechanism for TTFields, kinomics predicted the increased activity of platelet-derived growth-factor receptor alpha (PDGFRα). We demonstrated that the addition of the PDGFR inhibitor, crenolanib, to TTFields further reduced cell growth in comparison to either treatment alone. Collectively, our data suggest the efficacy of TTFields in vitro and identify common signaling responses to TTFields in TMZ-sensitive and -resistant populations, which may support more personalized medicine approaches. Full article

(1) Background: The objective of this analysis was to evaluate the device usage rates and patterns of use regarding Tumor-Treating Fields (TTFields) for patients with malignant pleural mesothelioma (MPM) throughout the US. (2) Methods: We evaluated de-identified data from 33 patients with MPM enrolled in FDA-required HDE protocols at 14 institutions across the US from September 2019 to March 2022. (3) Results: The median number of total TTFields usage days was 72 (range: 6–649 days), and the total treatment duration was 160 months for all patients. A low usage rate (defined as less than 6 h per day, 25%) was observed in 34 (21.2%) months. The median TTFields usage in the first 3 months was 12 h per day (range: 1.9–21.6 h), representing 50% (range: 8–90%) of the potential daily duration. The median TTFields usage after 3 months decreased to 9.1 h per day (range: 3.1–17 h), representing 38% (range: 13–71%) of the daily duration, and was lower than usage in the first 3 months (p = 0.01). (4) Conclusions: This study represents the first multicenter analysis of real-world TTFields usage based on usage patterns for MPM patients in clinical practice. The real-world usage level was lower than the suggested daily usage. Further initiatives and guidelines should be developed to evaluate the impact of this finding on tumor control. Full article

Epithelioid glioblastoma (EGBM, classified as glioblastoma, IDH wild type, grade 4 according to the fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) (WHO CNS5)) is a highly aggressive malignancy, with a median progression-free survival (mPFS) of about 6 months in adults. The application of tumor-treating fields (TTFields, possessing anti-cancer capabilities via anti-mitotic effects) in the maintenance of temozolomide (TMZ) chemotherapy showed a benefit for prolonging the mPFS of newly diagnosed glioblastoma (GBM) for patients for up to 6.9 months in the EF-14 clinical trial (NCT00916409). However, studies focusing on the effect of TTFields in EGBM treatment are very limited due to the rarity of EGBM. Here, we have reported a case of a 28-year-old male (recurrent left-sided limb twitching for 1 month and dizziness for 1 week) diagnosed with EGBM. A right frontal lobe occupancy was detected by magnetic resonance imaging (MRI), and a total tumor resection was performed. Meanwhile, a postoperative histopathology test, including immunohistochemistry and molecular characterization, was conducted, and the results revealed a BRAF V600E mutation, no co-deletion of 1p and 19q, and negative O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Then, chemoradiotherapy was conducted, and TTFields and TMZ were performed sequentially. Notably, a long-term PFS of 34 months and a Karnofsky Performance Scale (KPS) of 90 were achieved by the patient on TTFields combined with TMZ, whose average daily usage of TTFields was higher than 90%. Full article

Tumor Treating Fields (TTFields) were incorporated into the treatment of glioblastoma, the most malignant brain tumor, after showing an effect on progression-free and overall survival in a phase III clinical trial. The combination of TTFields and an antimitotic drug might further improve this approach. Here, we tested the combination of TTFields with AZD1152, an Aurora B kinase inhibitor, in primary cultures of newly diagnosed (ndGBM) and recurrent glioblastoma (rGBM). AZD1152 concentration was titrated for each cell line and 5–30 nM were used alone or in addition to TTFields (1.6 V/cm RMS; 200 kHz) applied for 72 h using the inovitro™ system. Cell morphological changes were visualized by conventional and confocal laser microscopy. The cytotoxic effects were determined by cell viability assays. Primary cultures of ndGBM and rGBM varied in p53 mutational status; ploidy; EGFR expression and MGMT-promoter methylation status. Nevertheless; in all primary cultures; a significant cytotoxic effect was found following TTFields treatment alone and in all but one, a significant effect after treatment with AZD1152 alone was also observed. Moreover, in all primary cultures the combined treatment had the most pronounced cytotoxic effect in parallel with morphological changes. The combined treatment of TTFields and AZD1152 led to a significant reduction in the number of ndGBM and rGBM cells compared to each treatment alone. Further evaluation of this approach, which has to be considered as a proof of concept, is warranted, before entering into early clinical trials. Full article