An update on the molecular biology of glioblastoma, with clinical implications and progress in its treatment

Cancer Communications, Год журнала: 2022, Номер 42(11), С. 1083 - 1111

Опубликована: Сен. 21, 2022

Abstract Glioblastoma multiforme (GBM) is the most aggressive and common malignant primary brain tumor. Patients with GBM often have poor prognoses, a median survival of ∼15 months. Enhanced understanding molecular biology central nervous system tumors has led to modifications in their classifications, recent which classified these into new categories made some changes nomenclature grading system. This review aims give panoramic view last 3 years’ findings glioblastoma characterization, its heterogeneity, current advances treatment. Several parameters been used achieve an accurate personalized characterization patients, including epigenetic, genetic, transcriptomic metabolic features, as well age‐ sex‐related patterns involvement several noncoding RNAs progression. Astrocyte‐like neural stem cells outer radial glial‐like from subventricular zone proposed agents involved IDH‐wildtype origin, but this remains controversial. metabolism characterized by upregulation PI3K/Akt/mTOR signaling pathway, promotion glycolytic flux, maintenance lipid storage, other features. also contributes glioblastoma's resistance conventional therapies. Tumor hallmark GBM, shown affect genetic expression, modulation pathways, immune evasion. GBM's invasion potential modulated cell‐to‐cell crosstalk within tumor microenvironment altered expressions specific genes, such ANXA2 , GBP2 FN1 PHIP GLUT3 . Nevertheless, rising number active clinical trials illustrates efforts identify targets drugs treat malignancy. Immunotherapy still relevant for research purposes, given amount ongoing based on strategy neoantigen nucleic acid‐based vaccines are gaining importance due antitumoral activity inducing response. Furthermore, there focused axis, angiogenesis, heterogeneity developing molecular‐targeted therapies against GBM. Other strategies, nanodelivery computational models, may improve drug pharmacokinetics prognosis patients

Язык: Английский

---

Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Май 8, 2024

Abstract Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, exploration of emerging modalities such as immunotherapy integration medicine engineering technology therapy, efficacy these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny inhibitory milieu within GBM has underscored significance cellular constituents microenvironment their interactions with cells neurons. Novel immune targeted therapy strategies have emerged, offering promising avenues for advancing treatment. One pivotal mechanism orchestrating immunosuppression involves aggregation myeloid-derived suppressor (MDSCs), glioma-associated macrophage/microglia (GAM), regulatory T (Tregs). Among these, MDSCs, though constituting minority (4–8%) CD45 + GBM, play central component fostering evasion propelling tumor progression, angiogenesis, invasion, metastasis. MDSCs deploy intricate mechanisms that adapt dynamic (TME). Understanding interplay between provides compelling basis This review seeks elucidate inherent explore existing targets, consolidate insights into MDSC induction contribution immunosuppression. Additionally, comprehensively surveys ongoing clinical trials potential strategies, envisioning future where targeting could reshape landscape GBM. Through synergistic other modalities, this approach can establish multidisciplinary, multi-target paradigm, ultimately improving prognosis quality life patients

Язык: Английский

---

Glioblastoma Therapy: Past, Present and Future

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(5), С. 2529 - 2529

Опубликована: Фев. 21, 2024

Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians researchers, no significant improvement in survival has achieved since Stupp protocol became standard care (SOC) 2005. Despite multimodality treatments, recurrence is almost universal with rates under 2 years after diagnosis. Here, we discuss recent progress our understanding GB pathophysiology, particular, importance glioma stem cells (GSCs), tumor microenvironment conditions, epigenetic mechanisms involved growth, aggressiveness recurrence. The discussion on therapeutic strategies first covers SOC treatment targeted therapies that shown to interfere different signaling pathways (pRB/CDK4/RB1/P16

Язык: Английский

---

An Overview of EGFR Mechanisms and Their Implications in Targeted Therapies for Glioblastoma

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(13), С. 11110 - 11110

Опубликована: Июль 5, 2023

Despite all of the progress in understanding its molecular biology and pathogenesis, glioblastoma (GBM) is one most aggressive types cancers, without an efficient treatment modality at moment, it remains largely incurable. Nowadays, frequently studied molecules with important implications pathogenesis classical subtype GBM epidermal growth factor receptor (EGFR). Although many clinical trials aiming to study EGFR targeted therapies have been performed, none them reported promising results when used glioma patients. The resistance these was proven be both acquired innate, seems influenced by a cumulus factors such as ineffective blood–brain barrier penetration, mutations, heterogeneity compensatory signaling pathways. Recently, shown that possesses kinase-independent (KID) pro-survival functions cancer cells. It imperative understand how pathways function they interconnect other Furthermore, identify mechanisms drug develop better tailored therapeutic agents.

Язык: Английский

---

Glioblastoma: An Update in Pathology, Molecular Mechanisms and Biomarkers

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(5), С. 3040 - 3040

Опубликована: Март 6, 2024

Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor in adults. Despite important advances understanding molecular pathogenesis biology this past decade, prognosis for GBM patients remains poor. characterized by aggressive biological behavior high degrees inter-tumor intra-tumor heterogeneity. Increased cellular heterogeneity may not only help more accurately define specific subgroups precise diagnosis but also lay groundwork successful implementation targeted therapy. Herein, we systematically review key achievements pathogenesis, mechanisms, biomarkers decade. We discuss pathology GBM, including genetics, epigenetics, transcriptomics, signaling pathways. that have potential clinical roles. Finally, new strategies, current challenges, future directions discovering therapeutic targets will be discussed.

Язык: Английский

---

Transferrin receptor 1 targeted nanomedicine for brain tumor therapy

Biomaterials Science, Год журнала: 2023, Номер 11(10), С. 3394 - 3413

Опубликована: Янв. 1, 2023

This review summarizes the latest advances in TfR1-targeted nanomedicine for brain tumor therapy.

Язык: Английский

---

Targeted Glioma Therapy—Clinical Trials and Future Directions

Pharmaceutics, Год журнала: 2024, Номер 16(1), С. 100 - 100

Опубликована: Янв. 11, 2024

Glioblastoma multiforme (GBM) is the most common type of glioma, with a median survival 14.6 months post-diagnosis. Understanding molecular profile such tumors allowed development specific targeted therapies toward GBM, major role attributed to tyrosine kinase receptor inhibitors and immune checkpoint inhibitors. Targeted therapeutics are drugs that work by binding GBM-specific or overexpressed markers on tumor cellular surface therefore contain recognition moiety linked cytotoxic agent, which produces an antiproliferative effect. In this review, we have summarized available information used in clinical trials GBM current obstacles advances therapy concerning targets present cells, outlined efficacy endpoints for classes investigational drugs, discussed promising strategies towards increase drug GBM.

Язык: Английский

---

CRISPR-Cas9 library screening combined with an exosome-targeted delivery system addresses tumorigenesis/TMZ resistance in the mesenchymal subtype of glioblastoma

Theranostics, Год журнала: 2024, Номер 14(7), С. 2835 - 2855

Опубликована: Янв. 1, 2024

Rationale:The large-scale genomic analysis classifies glioblastoma (GBM) into three major subtypes, including classical (CL), proneural (PN), and mesenchymal (MES) subtypes.Each of these subtypes exhibits a varying degree sensitivity to the temozolomide (TMZ) treatment, while prognosis corresponds molecular genetic characteristics tumor cell type.Tumors with MES features are predominantly characterized by NF1 deletion/alteration, leading sustained activation RAS PI3K-AKT signaling pathways in GBM tend acquire drug resistance, resulting worst compared other (PN CL).Here, we used CRISPR/Cas9 library screening technique detect TMZ-related gene targets that might play roles acquiring using overexpressed KRAS-G12C mutant lines.The study identified key therapeutic strategy address chemoresistance against subtype GBM.Methods: The CRISPR-Cas9 was discover genes associated TMZ resistance U87-KRAS (U87-MG which is mutant) cells.The patient-derived primary line TBD0220 for experimental validations vivo vitro.Chromatin isolation RNA purification (ChIRP) chromatin immunoprecipitation (ChIP) assays were elucidate silencing mechanism suppressor MES-GBM subtype.The small-molecule inhibitor EPIC-0412 obtained through high-throughput screening.Transmission electron microscopy (TEM) characterize exosomes (Exos) secreted cells after treatment.Blood-derived Exos-based targeted delivery siRNA, TMZ, optimized tailor personalized therapy vivo.Results: Using genome-wide screening, found ERBIN could be epigenetically regulated cells.ERBIN overexpression inhibited downstream proliferation invasion effects cells.EPIC-0412 treatment EMT progression upregulating expression both vitro vivo.Genome-wide also RASGRP1(Ras guanine nucleotide-releasing protein 1) VPS28(Vacuolar sorting-associated 28) as synthetically lethal response cells.We RASGRP1 activated RAS-mediated DDR pathway promoting RAS-GTP transformation.VPS28 promoted Exos secretion decreased intracellular concentration system encapsulating drugs siRNAs together showed powerful effect vivo. Ivyspring

Язык: Английский

---

IDO1 inhibits ferroptosis by regulating FTO-mediated m6A methylation and SLC7A11 mRNA stability during glioblastoma progression

Cell Death Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 25, 2025

Язык: Английский

---

GAS41 promotes ITGA4-mediated PI3K/Akt/mTOR signaling pathway and glioma tumorigenesis

Biochemical Pharmacology, Год журнала: 2025, Номер unknown, С. 116747 - 116747

Опубликована: Янв. 1, 2025

Язык: Английский

---