-
Biochemical and Biophysical Research... Sep 2023In the surgical management of glioblastoma, a highly aggressive and incurable type of brain cancer, identification and treatment of residual tissue is the most common...
BACKGROUND
In the surgical management of glioblastoma, a highly aggressive and incurable type of brain cancer, identification and treatment of residual tissue is the most common site of disease recurrence. Monitoring and localized treatment are achieved with engineered microbubbles (MBs) by combining ultrasound and fluorescence imaging with actively targeted temozolomide (TMZ) delivery.
METHODS
The MBs were conjugated with a near-infrared fluorescence probe CF790, cyclic pentapeptide bearing the RGD sequence and a carboxyl-temozolomide, TMZA. The efficiency of adhesion to HUVEC cells was assessed in vitro in realistic physiological conditions of shear rate and vascular dimensions. Cytotoxicity of TMZA-loaded MBs on U87 MG cells and IC50 were assessed by MTT tests.
RESULTS
We report on the design of injectable poly(vinyl alcohol) echogenic MBs designed as a platform with active targeting ability to tumor tissues, by tethering on the surface a ligand having the tripeptide sequence, RGD. The biorecognition of RGD-MBs onto HUVEC cells is quantitatively proved. Efficient NIR emission from the CF790-decorated MBs was successfully detected. The conjugation on the MBs surface of a specific drug as TMZ is achieved. The pharmacological activity of the coupled-to-surface drug is preserved by controlling the reaction conditions.
CONCLUSIONS
We present an improved formulation of PVA-MBs to achieve a multifunctional device with adhesion ability, cytotoxicity on glioblastoma cells and supporting imaging.
Topics: Humans; Glioblastoma; Temozolomide; Precision Medicine; Cell Line, Tumor; Neoplasm Recurrence, Local; Glioma; Optical Imaging; Oligopeptides; Microbubbles
PubMed: 37300942
DOI: 10.1016/j.bbrc.2023.05.089 -
Journal of Hematology & Oncology May 2024Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby... (Review)
Review
Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite the established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, and the exploration of emerging modalities such as immunotherapy and integration of medicine and engineering technology therapy, the efficacy of these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny of the inhibitory and immunosuppressive milieu within GBM has underscored the significance of cellular constituents of the GBM microenvironment and their interactions with malignant cells and neurons. Novel immune and targeted therapy strategies have emerged, offering promising avenues for advancing GBM treatment. One pivotal mechanism orchestrating immunosuppression in GBM involves the aggregation of myeloid-derived suppressor cells (MDSCs), glioma-associated macrophage/microglia (GAM), and regulatory T cells (Tregs). Among these, MDSCs, though constituting a minority (4-8%) of CD45 cells in GBM, play a central component in fostering immune evasion and propelling tumor progression, angiogenesis, invasion, and metastasis. MDSCs deploy intricate immunosuppressive mechanisms that adapt to the dynamic tumor microenvironment (TME). Understanding the interplay between GBM and MDSCs provides a compelling basis for therapeutic interventions. This review seeks to elucidate the immune regulatory mechanisms inherent in the GBM microenvironment, explore existing therapeutic targets, and consolidate recent insights into MDSC induction and their contribution to GBM immunosuppression. Additionally, the review comprehensively surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. Through the synergistic integration of immunotherapy with other therapeutic modalities, this approach can establish a multidisciplinary, multi-target paradigm, ultimately improving the prognosis and quality of life in patients with GBM.
Topics: Humans; Tumor Microenvironment; Brain Neoplasms; Myeloid-Derived Suppressor Cells; Glioma; Glioblastoma; Animals; Immunotherapy; T-Lymphocytes, Regulatory
PubMed: 38720342
DOI: 10.1186/s13045-024-01544-7 -
Biomaterials Science Mar 2024Glioma, as a disease of the central nervous system, is difficult to be treated due to the presence of the blood-brain barrier (BBB) that can severely hamper the efficacy... (Review)
Review
Glioma, as a disease of the central nervous system, is difficult to be treated due to the presence of the blood-brain barrier (BBB) that can severely hamper the efficacy of most therapeutic agents. Hence, drug delivery to glioma in an efficient, safe, and specifically targeted manner is the key to effective treatment of glioma. With the advances in nanotechnology, targeted drug delivery systems have been extensively explored to deliver chemotherapeutic agents, nucleic acids, and contrast agents. Among these nanocarriers, dendrimers have played a significant role since they possess highly branched structures, and are easy to be decorated, thus offering numerous binding sites for various drugs and ligands. Dendrimers can be designed to cross the BBB for glioma targeting, therapy or theranostics. In this review, we provide a concise overview of dendrimer-based carrier designs including dendrimer surface modification with hydroxyl termini, peptides, and transferrin . for glioma imaging diagnostics, chemotherapy, gene therapy, or imaging-guided therapy. Finally, the future perspectives of dendrimer-based glioma theraputics are also briefly discussed.
Topics: Humans; Blood-Brain Barrier; Dendrimers; Precision Medicine; Glioma; Drug Delivery Systems
PubMed: 38362780
DOI: 10.1039/d4bm00043a -
The Lancet. Oncology Sep 2023
Topics: Humans; Glioma; Genetic Therapy
PubMed: 37657467
DOI: 10.1016/S1470-2045(23)00389-3 -
Journal of Clinical Oncology : Official... Feb 2024Tumors of CNS are common in adolescents and young adults (AYAs). As the second leading cause of cancer-related death, CNS tumors in AYAs require improved clinical... (Review)
Review
Tumors of CNS are common in adolescents and young adults (AYAs). As the second leading cause of cancer-related death, CNS tumors in AYAs require improved clinical management. In this review, we discussed the current diagnostic approaches and recommended management strategies for malignant tumors in adult-type (IDH-mutant gliomas) and pediatric-type gliomas (pediatric high-grade gliomas), ependymoma and medulloblastoma, which commonly occur in AYAs. The impact of advanced molecular diagnostic approaches on the understanding of tumor biology of AYA CNS tumors is emphasized. To enhance participation in clinical trials, which poses a unique challenge in AYAs with CNS tumors, we propose encouraging referrals to neuro-oncology specialty care and improving collaboration between oncologists who care for both pediatric and adult patients. This will ensure better representation of AYA patients in research studies. Finally, we discussed the importance of considering neurocognitive and psychological function in AYAs with CNS tumor.
Topics: Humans; Adolescent; Young Adult; Child; Neoplasms; Central Nervous System Neoplasms; Glioma; Medulloblastoma; Ependymoma; Cerebellar Neoplasms
PubMed: 38064656
DOI: 10.1200/JCO.23.01747 -
Frontiers in Immunology 2024Despite aggressive standard-of-care therapy, including surgery, radiation, and chemotherapy, glioblastoma recurrence is almost inevitable and uniformly lethal....
INTRODUCTION
Despite aggressive standard-of-care therapy, including surgery, radiation, and chemotherapy, glioblastoma recurrence is almost inevitable and uniformly lethal. Activation of glioma-intrinsic Wnt/β-catenin signaling is associated with a poor prognosis and the proliferation of glioma stem-like cells, leading to malignant transformation and tumor progression. Impressive results in a subset of cancers have been obtained using immunotherapies including anti-CTLA4, anti-PD-1, and anti-PD-L1 or chimeric antigen receptor (CAR) T cell therapies. However, the heterogeneity of tumors, low mutational burden, single antigen targeting, and associated antigen escape contribute to non-responsiveness and potential tumor recurrence despite these therapeutic efforts. In the current study, we determined the effects of the small molecule, highly specific Wnt/CBP (CREB Binding Protein)/β-catenin antagonist ICG-001, on glioma tumor cells and the tumor microenvironment (TME)-including its effect on immune cell infiltration, blood vessel decompression, and metabolic changes.
METHODS
Using multiple glioma patient-derived xenografts cell lines and murine tumors (GL261, K-Luc), we demonstrated cytostatic effects and a switch from proliferation to differentiation after treatment with ICG-001.
RESULTS
In these glioma cell lines, we further demonstrated that ICG-001 downregulated the CBP/β-catenin target gene a hallmark of Wnt/CBP/β-catenin inhibition. We found that in a syngeneic mouse model of glioma (K-luc), ICG-001 treatment enhanced tumor infiltration by CD3 and CD8 cells with increased expression of the vascular endothelial marker CD31 (PECAM-1). We also observed differential gene expression and induced immune cell infiltration in tumors pretreated with ICG-001 and then treated with CAR T cells as compared with single treatment groups or when ICG-001 treatment was administered after CAR T cell therapy.
DISCUSSION
We conclude that specific Wnt/CBP/β-catenin antagonism results in pleotropic changes in the glioma TME, including glioma stem cell differentiation, modulation of the stroma, and immune cell activation and recruitment, thereby suggesting a possible role for enhancing immunotherapy in glioma patients.
Topics: Humans; Animals; Mice; beta Catenin; Wnt Signaling Pathway; Neoplasm Recurrence, Local; Immunotherapy; Glioma; Tumor Microenvironment
PubMed: 38449858
DOI: 10.3389/fimmu.2024.1342625 -
Biomedicine & Pharmacotherapy =... Sep 2023Glioblastoma (GBL) is the most common (60-70% of primary brain tumours) and the most malignant of the glial tumours. Although current therapies remain palliative, they... (Review)
Review
Glioblastoma (GBL) is the most common (60-70% of primary brain tumours) and the most malignant of the glial tumours. Although current therapies remain palliative, they have been proven to prolong overall survival. Within an optimal treatment regimen (incl. surgical resection, radiation therapy, and chemotherapy) temozolomide as the current anti-GBL first-line chemotherapeutic has increased the median overall survival to 14-15 months, and the percentage of patients alive at two years has been reported to rise from 10.4% to 26.5%. Though, the effectiveness of temozolomide chemotherapy is limited by the serious systemic, dose-related side effects. Therefore, the ponderation regarding novel treatment methods along with innovative formulations is crucial to emerging the therapeutic potential of the widely used drug simultaneously reducing the drawbacks of its use. Herein the complex temozolomide application restrictions present at different levels of therapy as well as, the currently proposed strategies aimed at reducing those limitations are demonstrated. Approaches increasing the efficacy of anti-GBL treatment are addressed. Our paper is focused on the most recent developments in the field of nano/biomaterials-based systems for temozolomide delivery and their functionalization towards more effective blood-brain-barrier crossing and/or tumour targeting. Appropriate designing accounting for the physical and chemical features of formulations along with distinct routes of administration is also discussed. In addition, considering the multiple resistance mechanisms, the molecular heterogeneity and the evolution of tumour the purposely selected delivery methods, the combined therapeutic approaches and specifically focused on GBL cells therapies are reviewed.
Topics: Humans; Temozolomide; Dacarbazine; Brain Neoplasms; Glioblastoma; Glioma; Antineoplastic Agents, Alkylating
PubMed: 37459661
DOI: 10.1016/j.biopha.2023.115174 -
International Journal of Molecular... Dec 2023Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose... (Review)
Review
Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma.
Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose metabolism. Moreover, oncogenic signaling pathways induce the expression of metabolic genes, increasing the metabolic enzyme activities and thus the critical biosynthetic pathways to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates that are essential to accomplish the biosynthetic needs of glioma cells. In this review, we aim to explore how dysregulated metabolic enzymes and their metabolites from primary metabolism pathways in glioblastoma (GBM) such as glycolysis and glutaminolysis modulate anabolic and catabolic metabolic pathways as well as pro-oncogenic signaling and contribute to the formation, survival, growth, and malignancy of glioma cells. Also, we discuss promising therapeutic strategies by targeting the key players in metabolic regulation. Therefore, the knowledge of metabolic reprogramming is necessary to fully understand the biology of malignant gliomas to improve patient survival significantly.
Topics: Humans; Glioblastoma; Glutamine; Metabolic Reprogramming; Glycolysis; Glioma; Signal Transduction; Apoptosis; Cell Proliferation
PubMed: 38139462
DOI: 10.3390/ijms242417633 -
Aging Sep 2023Glioma is the most frequent primary tumor of the central nervous system. The high heterogeneity of glioma tumors enables them to adapt to challenging environments,...
BACKGROUND
Glioma is the most frequent primary tumor of the central nervous system. The high heterogeneity of glioma tumors enables them to adapt to challenging environments, leading to resistance to treatment. Therefore, to detect the driving factors and improve the prognosis of glioma, it is essential to have a comprehensive understanding of the genomic heterogeneity, stemness, and immune microenvironment of glioma.
METHODS
We classified gliomas into various subtypes based on stemness, genomic heterogeneity, and immune microenvironment consensus clustering analysis. We identified risk hub genes linked to heterogeneous characteristics using WGCNA, LASSO, and multivariate Cox regression analysis and utilized them to create an effective risk model.
RESULTS
We thoroughly investigated the genomic heterogeneity, stemness, and immune microenvironment of glioma and identified the risk hub genes RAB42, SH2D4A, and GDF15 based on the TCGA dataset. We developed a risk model utilizing these genes that can reliably predict the prognosis of glioma patients. The risk signature showed a positive correlation with T cell exhaustion and increased infiltration of immunosuppressive cells, and a negative correlation with the response to immunotherapy. Moreover, we discovered that SH2D4A, one of the risk hub genes, could stimulate the migration and proliferation of glioma cells.
CONCLUSIONS
This study identified risk hub genes and established a risk model by analyzing the genomic heterogeneity, stemness, and immune microenvironment of glioma. Our findings will facilitate the diagnosis and prediction of glioma prognosis and may lead to potential treatment strategies for glioma.
Topics: Humans; Tumor Microenvironment; Genomics; Prognosis; Immunotherapy; Cluster Analysis; Glioma
PubMed: 37698534
DOI: 10.18632/aging.205018 -
Neuro-oncology Aug 2023Patients with diffuse glioma are at high risk of developing venous thromboembolism (VTE) over the course of the disease, with up to 30% incidence in patients with...
Patients with diffuse glioma are at high risk of developing venous thromboembolism (VTE) over the course of the disease, with up to 30% incidence in patients with glioblastoma (GBM) and a lower but nonnegligible risk in lower-grade gliomas. Recent and ongoing efforts to identify clinical and laboratory biomarkers of patients at increased risk offer promise, but to date, there is no proven role for prophylaxis outside of the perioperative period. Emerging data suggest a higher risk of VTE in patients with isocitrate dehydrogenase (IDH) wild-type glioma and the potential mechanistic role of IDH mutation in the suppression of production of the procoagulants tissue factor and podoplanin. According to published guidelines, therapeutic anticoagulation with low molecular weight heparin (LMWH) or alternatively, direct oral anticoagulants (DOACs) in patients without increased risk of gastrointestinal or genitourinary bleeding is recommended for VTE treatment. Due to the elevated risk of intracranial hemorrhage (ICH) in GBM, anticoagulation treatment remains challenging and at times fraught. There are conflicting data on the risk of ICH with LMWH in patients with glioma; small retrospective studies suggest DOACs may convey lower ICH risk than LMWH. Investigational anticoagulants that prevent thrombosis without impairing hemostasis, such as factor XI inhibitors, may carry a better therapeutic index and are expected to enter clinical trials for cancer-associated thrombosis.
Topics: Humans; Heparin, Low-Molecular-Weight; Venous Thromboembolism; Retrospective Studies; Anticoagulants; Neoplasms; Glioma; Glioblastoma; Biology
PubMed: 37100086
DOI: 10.1093/neuonc/noad059