Search Results (2,188)

Glioblastoma (GBM) is a highly aggressive brain tumor with limited therapeutic options due to its invasive nature, therapeutic resistance, and the challenge of drug delivery across the blood–brain barrier (BBB). Mesenchymal stem cells (MSCs), owing to their tumor tropic properties and ability to cross the BBB, offer a promising platform for targeted anti-cancer delivery. We previously engineered MSCs to express CD::UPRT and TRAIL, along with chemokine receptors to enhance tumor homing (MSC-CD-TRAIL; BM03). This study evaluated the anti-tumor efficacy of BM03 using GBM patient-derived organoids (GBOs), clinically relevant in vitro models. Using a GBO–MSC co-culture system, BM03 significantly increased cell death and reduced viability in GBOs from four GBM patients compared with controls and MSC-WT groups. In 3D invasion assays, BM03-treated GBOs showed markedly reduced invasive outgrowth, accompanied by downregulation of EMT markers (Zeb1 and Snail) and stem-like markers (Olig2 and Sox2), particularly in invasive regions. GFAP expression remained unchanged, suggesting selective targeting of tumor stem-like cells. Live-cell imaging further demonstrated BM03 infiltration into GBOs, which was associated with increased apoptosis, as evidenced by elevated cleaved caspase-3 levels. These findings provide organoid-based preclinical evidence supporting further evaluation of BM03 as an MSC-based therapeutic strategy for GBM. Full article

Brain tumors are the most common solid malignancies in children and the leading cause of cancer-related mortality in this age group. Cancer immunotherapy has shown a lot of promise in the treatment of both adult and pediatric cancers. In this review, we summarize the use of immunotherapies in the treatment of pediatric brain tumors with special emphasis on CAR T cells, Immune checkpoint inhibitors and oncolytic viral therapy. Full article

Background/Objectives: Pediatric solid tumors (PST) are a biologically distinct group of malignancies whose developmental origins and molecular drivers differ substantially from those of adult cancers, with direct implications for therapeutic strategy and clinical outcome. This review synthesizes current evidence on molecular pathogenesis, tumor microenvironment biology, and the structural conditions that shape access to care across select PST. Methods: A narrative review of peer-reviewed literature was conducted primarily using PubMed, supplemented by Google Scholar, covering publications from 2000 to 2025. Tumor types were selected based on their prevalence in the pediatric population and the availability of evidence addressing both molecular features and health disparities. Body: Across eight tumor types (neuroblastoma, Ewing sarcoma, pediatric brain tumors, rhabdomyosarcoma, Wilms tumor, retinoblastoma, osteosarcoma, and chondrosarcoma), recurrent molecular alterations including MYCN amplification, EWS-FLI1 fusions, PAX-FOXO1 rearrangements and IDH 1/2 mutations emerge as central determinants of disease behavior and eligibility for treatment. The tumor microenvironment manifests as a shared mediator of immune exclusion and therapeutic resistance across tumor types, with, but not limited to, tumor-associated macrophages, myeloid-derived suppressor cells, and checkpoint molecule expression, identified as recurrent features influencing treatment response. Immunotherapeutic strategies have shown variable efficacy across PST, with the most consistent clinical benefit established in neuroblastoma. A critical and underappreciated pattern stands out across tumor types: children carrying the most aggressive molecular subtypes are disproportionately those with the least access to therapies those subtypes demand, emphasizing an overlap of biological and structural disadvantage that is also amplified in low- and middle-income countries, where late-stage presentation, treatment abandonment and limited access to molecular diagnostics compound the biological disadvantage. Conclusions: Within the eight PST reviewed, the most aggressive molecular subtypes and the greatest structural disadvantages converge in the same children; those carrying MYCN amplification, PAX-FOXO1 fusions, or EWS-FLI1 fusions are disproportionately those with the least access to the therapies their biology demands. Genomic and immunologic advances will only reach their full clinical potential when paired with inclusive trial data, diversified genomic databases, and most importantly, equitable access to biomarker-specialized therapies across all populations. Full article

Background/Objectives: Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, and elucidating the molecular determinants of its malignant progression is essential for improving patient outcomes. NTAN1 encodes N-terminal asparagine amidase 1, a component of the N-degron pathway involved in selective protein turnover; however, its role in GBM remains unclear. This study aimed to investigate the clinical significance and biological function of NTAN1 in GBM. Methods: Integrated analyses of The Cancer Genome Atlas (TCGA) transcriptomic and clinical data were performed, together with tissue microarray validation, to assess the association between NTAN1 expression and prognosis in GBM. Immunohistochemical analysis of GBM specimens was conducted to evaluate NTAN1 protein expression. Functional studies, including NTAN1 knockdown and overexpression experiments, were used to examine its effects on GBM cell proliferation, clonogenic growth, migration, and invasion. An orthotopic GBM model was established to assess the effect of NTAN1 inhibition on tumor growth. Transcriptomic analysis was further performed to explore the molecular changes associated with NTAN1 knockdown. Results: Elevated NTAN1 expression was associated with poor survival in GBM. Immunohistochemical analysis further demonstrated that high NTAN1 protein expression predicted unfavorable prognosis. Functional studies showed that NTAN1 knockdown inhibited GBM cell proliferation, clonogenic growth, migration, and invasion, whereas NTAN1 overexpression promoted these malignant phenotypes. In an orthotopic GBM model, NTAN1 inhibition significantly reduced tumor volume. Transcriptomic analysis showed that NTAN1 knockdown was associated with reduced expression of invasion-related genes, including SPINK1, MMP1, and LIF, and with enrichment changes in inflammation-associated pathways, suggesting that NTAN1 may promote GBM progression through pro-invasive molecular programs. Conclusions: Collectively, these findings identify NTAN1 as a potential promoter of GBM malignant progression and a prognostic biomarker of poor outcome. Full article

Brain metastases represent a major clinical challenge in the management of non-small-cell lung cancer, particularly in patients with epidermal growth factor receptor mutations, constituting a leading cause of morbidity and mortality. In recent years, significant advancements have been made in both local therapies and systemic treatments. Nevertheless, managing central nervous system disease remains complex, encompassing challenges such as optimal therapy sequencing, resistance mechanisms, oligoprogression, the role of the blood–brain barrier, diagnostic strategies, and the influence of the brain tumor microenvironment. Despite advances, brain metastases in non-small-cell lung cancer remain an unmet need. Local treatments like radiotherapy are effective but carry risks of long-term neurological side effects, while the number and burden of brain metastases remain key prognostic factors. Surgical resection may be considered even in patients with multiple brain metastases to improve clinical status, enable further therapy, and enhance survival and quality of life. With the extension of survival afforded by systemic therapies, optimizing the balance between treatment efficacy and quality of life has become critical. Integrating patient perspectives is essential in navigating these complex clinical decisions. Full article

Background/Objectives: Glioblastoma (GBM) is the most lethal primary brain malignancy in adults, with a median overall survival of approximately 15 months. Temozolomide (TMZ) resistance develops in virtually all patients, and no second-line regimen has improved outcomes over the past two decades. The DNA methyltransferase inhibitor decitabine (DAC) has attracted interest as a chemosensitizer, but whether it directly reverses the TMZ-resistance transcriptome or operates through distinct, complementary mechanisms has not been tested at multi-omics resolution. Methods: We performed an integrative six-layer multi-omics analysis across five public GEO datasets (bulk RNA-seq, EPIC 850K methylation, and 21,676 single cells) re-purposed from studies conducted for unrelated aims, formally tested DAC-mediated reversal of the TMZ-resistance transcriptome across 11,707 genes, mapped pharmacogenomic targets with DGIdb v5, and built an exploratory, hypothesis-generating 11-gene prognostic model internally validated in TCGA-GBM (n = 166) and externally tested in the independent CPTAC-GBM cohort (n = 96). Results: DAC reprogrammed transcription across 1114–1882 differentially expressed genes per cohort and reactivated 146 direct epigenetic targets, identifying INPP5D/SHIP1 as the top-ranked direct epigenetic-reactivation target. Genome-wide reversal analysis across 11,707 co-detected genes showed a negligible effect (Spearman ρ = 0.073), but single-cell analysis revealed significant per-cell attenuation of MES-like and stem-like programs (Δ = −0.071 and −0.135, respectively; both p < 0.001). The 11-gene risk model achieved a Harrell’s C-index of 0.706 (apparent); after correcting for the two-stage gene selection with a full-pipeline bootstrap, the optimism-corrected C-index was 0.63, and external validation in an independent cohort (CPTAC-GBM, n = 96) showed only near-chance discrimination (C-index 0.55), indicating that the signature does not generalize and is exploratory. Pharmacogenomic mapping yielded 734 unique therapeutic agents (230 FDA-approved) across 69 druggable targets after excluding AR. Most of these agents are not GBM-directed, so this catalog-level mapping is hypothesis-generating rather than a set of therapeutic recommendations. Conclusions: DAC does not broadly reverse the TMZ-resistant transcriptome but acts through three complementary mechanisms: epigenetic reactivation of INPP5D/SHIP1, cancer-testis-antigen and type I interferon induction, and per-cell attenuation of mesenchymal–stem-like transcriptional intensity, supporting hypotheses for rationally designed DAC-based combination therapy in TMZ-resistant GBM. Full article

Brain cancer is a highly aggressive disease with limited treatment options, highlighting the need for reliable preclinical models for drug discovery. This study aimed to isolate and characterize Saudi patient-derived primary brain cancer cells and assess the anticancer activity of novel compounds developed in-house. Sixteen tumor samples from Saudi patients were processed to establish primary brain cancer cultures and One Normal Tissue (Control). The cells were successfully isolated and maintained under optimized conditions, with their morphology and growth characteristics monitored. Molecular analysis confirmed the expression of key tumor and neural markers. The anticancer activity of selected compounds, KCO69, KCO70, and KCO129, was tested at various concentrations using the MTT and CellTiter-Glo Luminescent Cell Viability Assay. All compounds caused a concentration-dependent reduction in cell viability, with the strongest effects seen at 25 µM. Among them, compound 70 showed the most significant antiproliferative activity, while compounds KCO69 and KCO129 exhibited moderate effects. Variability in treatment response among cultures reflected the inherent heterogeneity of patient-derived tumors. Overall, establishing primary brain cancer cell models from Saudi patients offers a valuable platform for preclinical drug screening and supports further research on these compounds as potential therapies for brain cancer. Full article

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy associated with rapid proliferation, early metastatic spread, and poor long-term survival. Despite high initial responsiveness to chemotherapy and radiotherapy, most patients experience relapse, and therapeutic progress historically remained limited. Recent years, however, have seen meaningful advances that are beginning to reshape the management of SCLC. In extensive-stage disease, the incorporation of PD-L1 inhibitors into platinum-etoposide chemotherapy has established chemoimmunotherapy as the first-line standard, while underscoring the continued need for more durable disease control. In limited-stage SCLC, consolidation durvalumab following concurrent chemoradiotherapy has emerged as a practice-changing strategy with significant survival benefit. In relapsed disease, DLL3-targeted therapy has opened a new therapeutic avenue, with tarlatamab demonstrating clinically relevant efficacy in previously treated extensive-stage SCLC and becoming the first approved bispecific T-cell engager in this setting. Alongside these milestones, ongoing investigation is focused on maintenance strategies, novel targeted agents, biomarker development, molecular subtyping, and more effective integration of systemic therapy with radiation-based approaches. Nevertheless, resistance, toxicity management, central nervous system involvement, and the absence of validated predictive biomarkers remain major barriers to sustained progress. This narrative review examines recent advances in the biology and clinical management of SCLC, with emphasis on practice-changing developments, emerging therapeutic platforms, and future strategies aimed at improving outcomes in this historically difficult-to-treat disease. Full article

Glioblastoma remains the most lethal primary malignancy of the central nervous system, and the modest gains achieved with maximal surgery, radiotherapy and temozolomide have not been matched by the immune checkpoint inhibitors and antigen-specific vaccines that reshaped the treatment of many extracranial cancers. The recurrent disappointment of these approaches has been attributed less to a single molecular lesion than to a confluence of obstacles: profound intratumoural heterogeneity, a densely immunosuppressive and myeloid-rich microenvironment, sequestration and exhaustion of conventional T cells, and the practical difficulty of delivering effectors across the blood–brain barrier. Against this background, γδ T cells have attracted interest as an unconventional effector population that recognises transformed cells through stress-associated and metabolic cues rather than peptide–major histocompatibility complex (MHC) complexes, that kills in an MHC-unrestricted manner, and that can be expanded from healthy donors for allogeneic, off-the-shelf use with little expectation of graft-versus-host disease. This narrative review examines, with a deliberately critical lens, the biological rationale and the experimental evidence for γδ T cell-based immunotherapy of glioblastoma. We summarise the developmental biology and functional subsets of human γδ T cells, the natural killer group 2 member D (NKG2D)-, DNAX accessory molecule 1 (DNAM-1)- and T-cell-receptor-dependent mechanisms through which they engage glioblastoma cells and glioma stem-like cells, and the in vitro and animal-model studies that underpin the field, taking care not to overstate efficacy that has so far been demonstrated only in preclinical or early-phase settings. We then weigh the principal opportunities—locoregional and repeated dosing, combination with chemoradiotherapy, checkpoint blockade and antibody-based redirection—against barriers that include limited persistence, uncertain intratumoural trafficking, donor and manufacturing variability, and the unsettled requirements of potency testing and trial design. We give particular weight to what becomes of γδ T cells inside a hostile tumour—the exhaustion-like dysfunction that follows chronic stimulation, the oxygen and glucose dependence of their effector programme, the interleukin-17-polarising signals generated by activated microglia and by genotoxic therapy, and the confounding effect of corticosteroids—together with the engineering and pharmacological strategies proposed to counter them. The first peer-reviewed phase 1 report of intracranially delivered, drug-resistant γδ T cells has now appeared and documents tolerability in a small, single-arm cohort without establishing survival benefit. Throughout, γδ T cells are presented as a biologically plausible but still investigational strategy whose clinical value will be determined by adequately powered trials rather than by mechanistic appeal alone. Full article

A single-chain variable fragment (scFv) is an engineered antibody derivative that retains antigen-binding specificity while having a much smaller size than an antibody, improved tissue penetration, and enhanced versatility for genetic manipulation. When an scFv is fused with diverse protein payloads, multifunctional biologics can be created for targeted delivery and therapy. Over the past decade, scFv fusion proteins have gained significant traction in oncology, where they have been incorporated into immunotoxins, immunocytokines, bispecific antibodies, Chimeric Antigen Receptor (CAR)-T cells constructs, and immune cell engagers. In addition, advances in blood–brain barrier (BBB)-targeting strategies have enabled the exploration of scFv-based therapeutics for neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Despite promising preclinical and clinical outcomes, challenges such as structural instability, short half-life, immunogenicity, and manufacturing complexity remain. This review provides an in-depth and up-to-date overview of scFv fusion protein engineering and its therapeutic applications in cancer and neurodegenerative disorders. We also highlight the clinical translations and design principles of scFv fusion proteins. Full article

Glioblastoma (GBM) is a devastating brain tumor heavily reliant on metabolic reprogramming for survival. The DNA aptamer AS1411 specifically targets cell-surface nucleolin (NCL), a protein overexpressed in GBM; however, its precise metabolic consequences remain largely unexplored. This study investigated the direct impact of AS1411-mediated NCL inhibition on the lipidomic profile of U-87 glioblastoma cells. It was demonstrated that AS1411 treatment induced acute cytotoxicity within 24 h. Subsequently, high-resolution mass spectrometry (MS) lipidomics was utilized to identify the lipidomic rewiring triggered by AS1411. Significant changes, such as the upregulation and/or exclusive emergence of specific long-chain and highly polyunsaturated diacylglycerol (DAG), triacylglycerol (TAG), and glycerophospholipid (GP) species, were determined in the species-level analyses. Additionally, our findings revealed that AS1411 treatment induced substantial alterations that profoundly affected membrane biophysics by modifying lipid saturation and acyl chain lengths. An increase in fully saturated sphingomyelin (SM) and cholesteryl ester (CE) levels was observed, leading to the formation of saturated lipid microdomains (lipid rafts) in endosomal and ER membranes, which causes membrane rigidification and decreased fluidity. Our results also demonstrate that PEs containing long-chain polyunsaturated fatty acids (PUFAs)—the primary substrates for ferroptosis—were upregulated. While AS1411 subjects cancer cells to methuotic vacuolization stress, it simultaneously reduces internal structural membrane fluidity and renders the cells metabolically vulnerable to ferroptosis. In conclusion, these detailed lipidomic results indicate that AS1411 treatment proceeds strictly through targeted remodeling and an adaptive scaffolding response. Full article

Brain metastases have traditionally been investigated primarily with regard to interactions between tumor cells, the surrounding brain microenvironment, and associated inflammatory responses. By contrast, the presence of a true intratumoral stromal compartment in brain metastases has received much less attention, partly because the normal brain parenchyma lacks classical interstitial fibroblasts. However, recent histological, transcriptomic, and spatial studies suggest that at least a subset of carcinoma brain metastases contains fibroblast-like or cancer-associated fibroblast-like cells associated with collagen-rich extracellular matrix deposition. This raises a fundamental biological question: where do these cells come from? In this review, we discuss seven non-mutually exclusive hypotheses for the origin of cancer-associated fibroblast (CAF)-like cells in brain metastases, including pseudostromal mimics, meningeal or perivascular fibroblast-related cells, vascular mural cells, glial cells, cancer stem cell plasticity, tumor–stroma clusters, and circulating mesenchymal precursors. We compare the current findings for each hypothesis and highlight their major limitations. Overall, the available data support a heterogeneous and context-dependent model rather than a single universal origin. A better understanding of these stromal cell states may help refine the biological classification of brain metastases and support the future development of more targeted stromal therapies. Full article

Background/Objectives: Extra virgin olive oil (EVOO), a key component of the Mediterranean diet, has attracted research interest because olive-derived phenolics demonstrate potential anticancer activity in experimental models. This review summarizes evidence concerning whole EVOO, phenolic-enriched EVOO, olive phenolic extracts, and the isolated compounds hydroxytyrosol, oleuropein, oleocanthal, and oleacein. Methods: A structured narrative search of PubMed, Web of Science, ScienceDirect, and Google Scholar was conducted for literature published between 2015 and 2025. Evidence was reviewed for breast, prostate, colorectal, pancreatic, bone, oral, liver, gastric, hematological, and brain cancers. Comparatively limited evidence concerning cervical, endometrial, ovarian, melanoma, non-melanoma skin, and thyroid cancers was summarized separately. Results: The molecular evidence was derived primarily from cell culture and animal studies using isolated phenolics and concentrated extracts. Preclinical studies indicate that EVOO phenolics may demonstrate anticancer activity through multiple mechanisms, including antioxidant activity, anti-inflammatory effects, cell cycle arrest, induction of apoptosis, inhibition of metastasis, anti-angiogenic activity, and modulation of key signaling pathways, such as PI3K/AKT/mTOR, MAPK/ERK, NF-κB, JAK/STAT, Wnt/β-catenin, p53, and epithelial–mesenchymal transition-related pathways. Most molecular and pathway-level evidence was obtained using isolated phenolic compounds in cell culture or animal models, whereas evidence directly examining whole EVOO consumption was largely observational and substantially more limited. Experimental studies also reported that oleocanthal induced lysosomal membrane permeabilization, whereas hydroxytyrosol and oleuropein promoted mitochondria-mediated apoptosis. Furthermore, preclinical combination studies suggested enhanced tumor-cell sensitivity to selected chemotherapeutic, targeted, and immunotherapeutic agents. However, these effects have not been established in patients. Human evidence remains limited mainly to observational dietary associations and small exploratory interventions, with no conclusive demonstration of cancer prevention or therapeutic efficacy. Conclusions: Isolated EVOO-derived phenolic compounds demonstrated promising anticancer mechanisms in preclinical models. However, these results should not be directly extrapolated to dietary EVOO because experimentally administered doses, bioavailability, metabolism, and food-matrix interactions differ substantially from human dietary exposure. Therefore, well-designed studies using chemically characterized EVOO, pharmacokinetic investigations, and controlled human trials are required before dietary or clinical recommendations can be made. Full article

Cancer is responsible for systemic burdens, most notably cachexia and immunosuppression, that extend far beyond local tumor growth and collectively dictate poor outcomes. While often studied separately, these debilitating syndromes are deeply interconnected. On the basis of emerging evidence of growth differentiation factor 15 (GDF15)’s dual actions in immunity and metabolism, we propose that the stress-responsive hormone GDF15 is hijacked by tumors and repurposed as a central metaboceptive hub that integrates diverse oncogenic stress signals to launch a coordinated, dual pathological cascade. Systemically, it disrupts brain–body communication via glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL) activation in the brainstem, driving anorexia, metabolic rewiring, and progressive wasting of skeletal muscle and adipose tissue that define cachexia. GDF15 acts as a potent immunosuppressor within the local tumor microenvironment, impairing T cell cytotoxicity and increasing the abundance of regulatory T cells. Crucially, these effects are not parallel but interlinked, forming a self-reinforcing detrimental cycle that accelerates host deterioration and therapeutic failure. This positions the GDF15-GFRAL axis as a unique dual-benefit therapeutic target with the potential to simultaneously ameliorate cachexia, improve patient function and quality of life, and revitalize anti-tumor immunity. Reframing cancer through the lens of a hijacked metabolic sensing system provides an integrated perspective that transforms this formidable challenge of concurrent host wasting and immune evasion into a druggable opportunity, charting a course for novel host-directed therapies that restore systemic homeostasis. Full article

Chemotherapy is a treatment designed to contain or eradicate neoplastic cells; however, patients may experience various treatment-related adverse effects. Chemotherapy-related cognitive impairment (CRCI), clinically referred to as “chemobrain,” is a frequent complication with a duration ranging from months to years, affecting between 17% and 70% of cancer patients. These cognitive deficits not only impair social, educational, and occupational functioning but may also impact survival outcomes, possibly by interfering with medication adherence and health-related behaviors. Emerging evidence has converged on an integrative cascade in which chemotherapy-induced systemic inflammation, intestinal dysbiosis, blood–brain barrier disruption, microglial/astroglial activation, and impaired hippocampal neurogenesis act in sequence rather than as independent pathways. Underlying pathophysiological mechanisms include neuroinflammation, reduced neurogenesis, loss of dendritic spines, oxidative stress, hormonal changes, epigenetic modifications, and mitochondrial dysfunction. In contrast, repair mechanisms involve complex glial responses, particularly those of astrocytes and microglia. Emerging studies suggest a link between changes in the microbiome and cognitive decline, demonstrating the importance of bidirectional communication in the gut–brain axis. Current research seeks to determine appropriate tests to identify chemobrain. Therefore, several biomarkers, such as GFAP, S100β, and isoprostanes, have been proposed to assess chemobrain, alongside screening tools such as MoCA, MMSE, and CAB-CF, to evaluate cognitive impairment and enable early detection. Pharmacological candidates—including lithium, fluoxetine, methylphenidate, modafinil, metformin, agomelatine, and melatonin—as well as nutritional and lifestyle interventions such as physical exercise, omega-3 fatty acids, curcumin, probiotics, and traditional Chinese medicine formulations—have been investigated, predominantly in animal models. These remain candidate, not validated, therapies; clinical evidence in CRCI populations is limited, heterogeneous, or absent, and well-powered randomized controlled trials are required before any recommendation can be issued. However, optimal strategies for symptom improvement remain unclear, as various approaches have yielded mixed outcomes. This review provides a comprehensive overview of chemobrain, focusing on its molecular mechanisms, interactions with the gut–brain axis, and potential therapeutic targets to improve the quality of life for cancer survivors. Full article