Glioblastoma

P1, N=7, Recruiting, Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC) | Not yet recruiting --> Recruiting

In orthotopic GBM models, Cu3PdN@CR significantly suppresses tumor growth and prolongs survival without systemic toxicity. Collectively, this study establishes a BBB-permeable, US-augmented nanoplatform as a promising ferroptosis/cuproptosis-based strategy for effective GBM therapy.

Curcumin analogs demonstrate enhanced cytotoxicity in GBM cells, including temozolomide-resistant lines, through multi-target modulation of apoptosis, oxidative stress, oncogenic signaling, and glioma stem cell pathways...Therefore, curcumin analogs have demonstrated significant therapeutic potential as multi-targeting agents to address heterogeneity, treatment resistance, and invasiveness of GBM. However, to realize this potential, there is a need to improve their pharmacokinetics and permeability through the BBB.

Single-photon emission computed tomography imaging in tumor xenograft mouse models revealed no tumor retention of [123I]3 and [123I]4 due to rapid metabolism via radiodeiodination. Despite successful radiosynthesis and in vitro evaluation of iodine-123-labeled COX-2/5-LO inhibitors, improved inhibitory activity and stability are required for development of suitable radiotracers.

IDH1 mutations and their associated oncometabolite D-2HG remodel the innate lymphoid cell landscape in gliomas, driving an ILC3-biased phenotype with reduced checkpoint receptor expression. These findings identify ILCs as key modulators of glioma immunity and suggest that targeting innate immune pathways could complement existing immunotherapeutic approaches.

Mechanically, doxorubicin promotes the production of lactate through activating lactate dehydrogenase A (LDHA) to upregulate the transcription of inflammatory cytokines. Our study confirmed a new mechanism by which doxorubicin remodels the tumor microenvironment by promoting the glycolytic process and lactic acid production, suggesting that combining radiotherapy and temozolomide with doxorubicin chemotherapy may be a potential strategy for GBM treatment.

Temozolomide (TMZ) remains the standard chemotherapeutic agent but is frequently compromised by DNA-repair mechanisms, whereas tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis only in a subset of tumors due to strong intrinsic resistance...Gene set enrichment analysis (GSEA) and functional profiling further revealed distinct MuD-associated interactomes linked to receptor endocytosis and genotoxic-stress pathways. Together, these results uncover opposing roles of MuD in TRAIL- and TMZ-mediated cell death, with MuD suppressing apoptotic signaling in response to TRAIL while modulating p53-dependent genotoxic stress responses that influence TMZ-induced cytotoxicity in glioblastoma.

The results of this study demonstrated that ERN1 inhibition reduces BAG1 mRNA expression through the endoribonuclease activity of ERN1 and that protein kinase activity counteracts endoribonuclease in regulating the expression of BAG1 mRNA. Moreover, ERN1 inhibition also enhances the sensitivity of BAG1 mRNA expression to nutrient supply and hypoxia resulting in reduced resistance of glioblastoma cells.

This mRNA expression is upregulated under glutamine and glucose deprivation. Moreover, ERN1 inhibition strongly enhanced the sensitivity of PCK2 mRNA expression to glucose and glutamine deprivation as well as to hypoxia.

Our humanized GBM mouse model exhibited an immune cell signature similar to that of human recurrent GBM. This model is a valuable resource for analyzing the tumor immune landscape and assessing new therapies, particularly immunotherapies.

Our study highlights the importance of understanding tumor-specific factors that limit CAR T-cell response and using this information to design superior next-generation CAR T-cells. Specifically, we identify cytoskeleton remodeling and T cell motility as therapeutically actionable targets for future engineering approaches.