DNA-PK inhibition shows differential radiosensitization in orthotopic GBM PDX models based on DDR pathway deficits.

Glioblastoma (GBM) remains one of the most therapy-resistant malignancies with frequent local failures despite aggressive surgery, chemotherapy, and ionizing radiation (IR). Small molecule inhibitors of DNA-dependent protein kinase (DNA-PKi's) are potent radiosensitizers currently in clinical trials. Determining which patients may benefit from radiosensitization with DNA-PKi's is critical to avoid unnecessary increased risk of normal tissue toxicity.

Preclinical Systemic Pharmacokinetics, Dose Proportionality, and Central Nervous System Distribution of the ATM Inhibitor WSD0628, a Novel Radiosensitizer for the Treatment of Brain Tumors.

Radiation therapy, a standard treatment option for many cancer patients, induces DNA double-strand breaks (DSBs), leading to cell death. Ataxia telangiectasia mutated (ATM) kinase is a key regulator of DSB repair, and ATM inhibitors are being explored as radiosensitizers for various tumors, including primary and metastatic brain tumors. Efficacy of radiosensitizers for brain tumors may be influenced by a lack of effective drug delivery across the blood-brain barrier.

HTRA1 promotes EMT through the HDAC6/Ac-α-tubulin pathway in human GBM cells.

Background: The infiltrative nature of human gliomas renders complete surgical removal of tumors futile. Thus, illuminating mechanisms of their infiltrative properties may improve therapies and outcomes of glioma patients.

Methods: Comprehensive bioinformatic analyses of PRSS family were undertaken.

The dopamine receptor D1 inhibitor, SKF83566, suppresses GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interactions.

Background: Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs).

Metabolic modulation of histone acetylation mediated by HMGCL activates the FOXM1/β-catenin pathway in glioblastoma.

Background: Altered branched-chain amino acid (BCAA) metabolism modulates epigenetic modification, such as H3K27ac in cancer, thus providing a link between metabolic reprogramming and epigenetic change, which are prominent hallmarks of glioblastoma multiforme (GBM). Here, we identified mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase (HMGCL), an enzyme involved in leucine degradation, promoting GBM progression and glioma stem cell (GSC) maintenance.

Methods: In silico analysis was performed to identify specific molecules involved in multiple processes.

Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathway.

Background: Valtrate, a natural compound isolated from the root of Valeriana, exhibits antitumor activity in many cancers through different mechanisms. However, its efficacy for the treatment of glioblastoma (GBM), a tumor type with a poor prognosis, has not yet been rigorously investigated.

Methods: GBM cell lines were treated with valtrate and CCK-8, colony formation and EdU assays, flow cytometry, and transwell, 3D tumor spheroid invasion and GBM-brain organoid co-culture invasion assays were performed to assess properties of proliferation, viability, apoptosis and invasion/migration.

TRIM56 promotes malignant progression of glioblastoma by stabilizing cIAP1 protein.

Background: The tripartite motif (TRIM) family of proteins plays a key role in the developmental growth and therapeutic resistance of many tumors. However, the regulatory mechanisms and biological functions of TRIM proteins in human glioblastoma (GBM) are not yet fully understood. In this study, we focused on TRIM56, which emerged as the most differentially expressed TRIM family member with increased expression in GBM.

Scoring model based on the signature of non-m6A-related neoantigen-coding lncRNAs assists in immune microenvironment analysis and TCR-neoantigen pair selection in gliomas.

Background: Small peptides encoded by long non-coding RNAs (lncRNAs) have attracted attention for their various functions. Recent studies indicate that these small peptides participate in immune responses and antigen presentation. However, the significance of RNA modifications remains unclear.

Targeting the splicing factor NONO inhibits GBM progression through GPX1 intron retention.

Splicing factors are essential for nascent pre-mRNA processing and critical in cancer progression, suggesting that proteins with splicing functions represent potential molecular targets for cancer therapy. Here, we investigate the role of splicing factors in glioblastoma multiforme (GBM) progression and the possibility of targeting them for the treatment of the disease. The TCGA and CGGA public databases were used to screen for differentially expressed mRNA splicing factors.

Resibufogenin Targets the ATP1A1 Signaling Cascade to Induce G2/M Phase Arrest and Inhibit Invasion in Glioma.

Resibufogenin (RB) is a major active ingredient in the traditional Chinese medicine Chansu and has garnered considerable attention for its efficacy in the treatment of cancer. However, the anticancer effects and underlying mechanisms of RB on glioblastoma (GBM) remain unknown. Here, we found that RB induced G2/M phase arrest and inhibited invasion in a primary GBM cell line, P3#GBM, and two GBM cell lines, U251 and A172.

Knockdown of NUSAP1 inhibits cell proliferation and invasion through downregulation of TOP2A in human glioblastoma.

Nucleolar and spindle associated protein 1 (NUSAP1), an indispensable mitotic regulator, has been reported to be involved in the development, progression, and metastasis of several types of cancer. Here, we investigated the expression and biological function of NUSAP1 in human glioblastoma (GBM), an aggressive brain tumor type with largely ineffective treatment options. Analysis of the molecular data in CGGA, TCGA and Rembrandt datasets demonstrated that NUSAP1 was significantly upregulated in GBM relative to low grade gliomas and non-neoplastic brain tissue samples.

Biomarker subset analysis of a phase IIIb, open-label study of afatinib in EGFR tyrosine kinase inhibitor-naive patients with m+ non-small-cell lung cancer.

To explore the relationship between mutations in cfDNA and response to afatinib. In total, 64 patients from one Chinese site with locally advanced/metastatic m+ non-small-cell lung cancer, who received afatinib 40 mg once daily, were included. Overall, 33 (82.

A Phase IIIb Open-Label, Single-Arm Study of Afatinib in EGFR TKI-Naïve Patients with EGFRm+ NSCLC: Final Analysis, with a Focus on Patients Enrolled at Sites in China.

Background: Afatinib has been shown as a suitable option for the treatment of epidermal growth factor receptor mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC) in randomized controlled trials. However, patients treated in real-world clinical practice, including elderly patients, and those with brain metastases or poor Eastern Cooperative Oncology Group (ECOG) performance statuses, are often excluded from these studies.

Objective: To report the final results, with a particular focus on patients enrolled in China, from a prospective phase IIIb, "near real-world" study of afatinib in tyrosine kinase inhibitor (TKI)-naïve Asian patients with EGFRm+ NSCLC.

Thiabendazole Inhibits Glioblastoma Cell Proliferation and Invasion Targeting Mini-chromosome Maintenance Protein 2.

Thiabendazole (TBZ), approved by the US Food and Drug Administration (FDA) for human oral use, elicits a potential anticancer activity on cancer cells in vitro and in animal models. Here, we evaluated the efficacy of TBZ in the treatment of human glioblastoma multiforme (GBM). TBZ reduced the viability of GBM cells (P3, U251, LN229, A172, and U118MG) relative to controls in a dose- and time-dependent manner.