Solstara Research Report | 03-15-24

Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma

The New England Journal of Medicine

The study focuses on the use of CARv3-TEAM-E T cells to treat recurrent glioblastoma in three participants. The hypothesis being tested is whether CARv3-TEAM-E T cells can safely and effectively target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well as the wild-type EGFR protein, through secretion of a T-cell-engaging antibody molecule (TEAM). The results showed that treatment with CARv3-TEAM-E T cells did not result in adverse events greater than grade 3 or dose-limiting toxic effects. Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion. However, the responses were transient in two of the three participants.

Advanced Imaging in the Diagnosis and Response Assessment of High-Grade Glioma:Expert Panel Narrative Review

American Journal of Roentgenology

The study compares the outcomes observed under different experimental conditions or interventions, including DWI and diffusion tensor imaging, perfusion MRI techniques including dynamic susceptibility contrast (DSC), dynamic contrast-enhanced MRI, and arterial spin labeling, MR spectroscopy including assessment of 2-hydroxyglutarate (2HG) concentration, glucose- and amino acid (AA)-based PET, and amide proton transfer imaging. It identifies significant differences or similarities in the results between these conditions, with perfusion MRI being the most effective technique for differentiating recurrent tumor from post-treatment effects. The key findings support the recommendation that routine response assessment after HGG treatment should include perfusion MRI, particularly given the development of a consensus recommended DSC-MRI protocol. The study also highlights the need for increased availability of 2HG MRS and increased insurance funding in the United States for AA PET in order for these techniques to be widely adopted.

Multi-omic profiling of follicular lymphoma reveals changes in tissue architecture and enhanced stromal remodeling in high-risk patients

Cancer Cell

The study focuses on follicular lymphoma (FL), a generally incurable malignancy that evolves from developmentally blocked germinal center (GC) B cells. The hypothesis being tested is that dynamic interactions between tumor B cells and the tumor microenvironment (TME) contribute to the broad spectrum of clinical behaviors observed among FL patients. The methodology used for the experiment includes a multi-modal strategy that examines cell-intrinsic and -extrinsic factors governing progression and therapeutic outcomes in FL patients enrolled onto a prospective clinical trial. The primary objective of the study is to identify tumor-specific features and microenvironmental patterns enriched in individuals who experience early relapse, the most high-risk FL patients.

Unlocking the EGFR-mediated epitranscriptome: A pathway to novel therapies

Molecular Cell

The study investigates EGFR-driven epitranscriptomic reprogramming in glioblastoma and tests the hypothesis that the EGFR-ALKBH5-GCLM axis plays a crucial role in ferroptosis protection. The methodology involves in vitro experiments using human glioblastoma cells and mouse models, as well as in vivo experiments using xenograft models. The primary objective is to identify key mechanisms underlying ferroptosis protection in glioblastoma and to develop novel therapeutic strategies targeting the EGFR-ALKBH5-GCLM axis.

Mechanisms of action and resistance in histone methylation-targeted therapy

Nature

The study investigates the potency and mechanisms of action and resistance of the EZH1-EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma. It aims to understand the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumour cells in actual therapeutic settings. The primary objective of the study is to identify subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. The study uses single-cell analyses to show that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, including tumour suppressor genes. It also identifies acquired mutations at the PRC2-compound interface that result in the propagation of clones with increased H3K27me3 expression. The study identifies subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations.

High-throughput glycolytic inhibitor discovery targeting glioblastoma by graphite dots-assisted LDI mass spectrometry

Science advances

The study aims to discover a glycolytic inhibitor targeting glioblastoma using graphite dots-assisted laser desorption/ionization mass spectrometry as an integrated drug screening and pharmacokinetic platform (GLMSD). The study uses high-throughput virtual screening to narrow an initial library of 240,000 compounds down to the docking of 40 compounds and identifies five previously unknown chemical scaffolds as promising hexokinase-2 inhibitors. The best inhibitor (Compd 27) can regulate the reprogrammed metabolic pathway in U87 glioma cells for tumor suppression. It demonstrated highly effective therapy against glioblastoma by synergizing Compd 27 and temozolomide. The glycolytic inhibitor discovery can inspire personalized medicine targeting reprogrammed metabolisms of malignant tumors. GLMSD enables large, high-quality data for next-generation artificial intelligence-aided drug development.

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