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Exploiting a metabolic vulnerability in brain tumour stem cells using a brain-penetrant drug with safe profile

ABSTRACT: Exploiting a metabolic vulnerability in brain tumour stem cells using a brain-penetrant drug with safe profile

PROVIDER: PRJNA1200633 | ENA |

REPOSITORIES: ENA

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Exploiting a metabolic vulnerability in brain tumour stem cells using a brain-penetrant drug with safe profile

Project description:Exploiting a metabolic vulnerability in brain tumour stem cells using a brain-penetrant drug with safe profile

| PRJNA1065411 | ENA

Exploiting a metabolic vulnerability in brain tumour stem cells using a brain-penetrant drug with safe profile

Project description:Glioblastoma (GB) remains one of the most treatment refractory and fatal tumour in humans. GB contains a population of self-renewing stem cells, the brain tumour stem cells (BTSC) that are highly resistant to therapy and are at the origin of tumour relapse. Here, we report, for the first time, that mubritinib potently impairs stemness and growth of patient-derived BTSCs harboring different oncogenic mutations. Mechanistically, by employing bioenergetic assays and rescue experiments, we provide compelling evidence that mubritinib acts on complex I of the electron transport chain to impair BTSC stemness pathways, self-renewal and proliferation. Global gene expression profiling revealed that mubritinib alters the proliferative, neural-progenitor-like, and the cell-cycling state signatures. We employed in vivo pharmacokinetic assays to establish that mubritinib crosses the blood-brain barrier. Using preclinical models of patient-derived and syngeneic murine orthotopic xenografts, we demonstrated that mubritinib delays GB tumourigenesis, and expands lifespan of animals. Interestingly, its combination with radiotherapy offers survival advantage to animals. Strikingly, thorough toxicological and behavioral studies revealed that mubritinib does not induce any damage to normal cells and has a well-tolerated and safe profile. Our work warrants further exploration of this drug in in-human clinical trials for better management of GB tumours.

2024-05-15 | GSE253362 | GEO

Exploiting a metabolic vulnerability in brain tumour stem cells using a brain-penetrant drug with safe profile

2025-01-13 | GSE284766 | GEO

Quisinostat is a brain-penetrant radiosensitizer in glioblastoma

Project description:Quisinostat is a brain-penetrant radiosensitizer in glioblastoma

| PRJNA1006755 | ENA

Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib

Project description:Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib

| PRJNA1059002 | ENA

Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases

Project description:Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases

| PRJNA1014010 | ENA

Quisinostat is a brain-penetrant radiosensitizer in glioblastoma

Project description:In recent years, histone deacetylase inhibitors (HDACi) have garnered considerable interest for the treatment of adult and pediatric malignant brain tumors. However, owing to their broad-spectrum nature and inability to effectively penetrate the blood-brain barrier, HDACi have failed to provide significant clinical benefit to glioblastoma (GBM) patients to date. Moreover, global inhibition of HDACs results in widespread toxicity, highlighting the need for selective isoform targeting. While no isoform-specific HDACi are currently available, the second-generation hydroxamic acid-based HDACi quisinostat possesses sub-nanomolar specificity for class I HDAC isoforms, particularly HDAC1 and 2. Recently, we demonstrated that HDAC1 is the essential HDAC in GBM. Here, we panalyzed the neuro-pharmacokinetic, pharmacodynamic and radiation-sensitizing properties of quisinostat in preclinical models of GBM. We found that quisinostat is a well-tolerated and brain-penetrant molecule that significantly extended survival when administered in combination with radiation in vivo. The pharmacokinetic-pharmacodynamic-efficacy relationship was established by correlating free drug concentrations and evidence of target modulation in the brain with survival benefit. Together, these data provide a strong rationale for clinical development of quisinostat as a radiosensitizer for the treatment of GBM.

2023-11-23 | GSE241227 | GEO

A Brain Penetrant Mutant IDH1 Inhibitor Provides In Vivo Survival Benefit

Project description:A Brain Penetrant Mutant IDH1 Inhibitor Provides In Vivo Survival Benefit

| PRJNA415191 | ENA

Targeting glioblastoma with a brain penetrant drug that impairs brain tumour stem cells via NLE1-Notch1 complex

Project description:Targeting glioblastoma with a brain penetrant drug that impairs brain tumour stem cells via NLE1-Notch1 complex

| PRJNA1085335 | ENA

Regional vulnerability of brain white matter in VWM

Project description:Vanishing white matter (VWM) is a leukodystrophy that primarily manifests in young children. In this disease, the brain white matter is differentially affected in a predictable pattern with telencephalic brain areas being more severely affected, while others remain allegedly completely spared. Using high-resolution mass spectrometry-based proteomics, we investigated the proteome patterns of the severely affected white matter in the frontal lobe and normal appearing pons in VWM and control cases to identify molecular bases underlying regional vulnerability. By comparing VWM patients to controls, we identified disease-specific proteome patterns. We showed substantial pathogenic changes in both the frontal white matter and pons at the protein level. Side-by-side comparison of brain region-specific proteome patterns further revealed regional differences. We found that different cell types are affected in the VWM frontal white matter than in the pons. Gene ontology and pathway analyses identified involvement of region distinct biological processes, of which pathways implicated in cellular respiratory metabolism were overarching features. In the VWM frontal white matter, proteome changes were associated with decrease in glycolysis/gluconeogenesis and metabolism of various amino acids. By contrast, in the VWM pons white matter, we found a decrease in oxidative phosphorylation. Taken together, our data show that brain regions are affected in parallel in VWM, but to different degrees. We found region-specific involvement of different cell types and discovered that cellular respiratory metabolism is differently affected across white matter regions in VWM. These region-specific changes help explain regional vulnerability to pathology in VWM.

2023-06-28 | PXD040861 | Pride

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