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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: PRJNA1065411 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27562945_1.fastq.gz	Fastqsanger.gz
	SRR27562945_2.fastq.gz	Fastqsanger.gz
	SRR27562946_1.fastq.gz	Fastqsanger.gz
	SRR27562946_2.fastq.gz	Fastqsanger.gz
	SRR27562947_1.fastq.gz	Fastqsanger.gz

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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

| PRJNA1200633 | 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.

2025-01-13 | GSE284766 | GEO

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

2024-05-15 | GSE253362 | GEO

Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile

Project description:Glioblastoma is one of the most treatment-resistant and lethal cancers, with a subset of self-renewing brain tumour stem cells (BTSCs), driving therapy resistance and relapse. Here, we report that mubritinib effectively impairs BTSC stemness and growth. Mechanistically, bioenergetic assays and rescue experiments showed that mubritinib targets complex I of the electron transport chain, thereby impairing BTSC self-renewal and proliferation. Gene expression profiling and Western blot analysis revealed that mubritinib disrupts the AMPK/P27Kip1 pathway, leading to cell-cycle impairment. By employing in vivo pharmacokinetic assays, we established that mubritinib crosses the blood-brain barrier. Using preclinical patient-derived and syngeneic models, we demonstrated that mubritinib delays glioblastoma progression and extends animal survival. Moreover, combining mubritinib with radiotherapy or chemotherapy offers survival advantage to animals. Notably, we showed that mubritinib alleviates hypoxia, thereby enhancing ROS generation, DNA damage, and apoptosis in tumours when combined with radiotherapy. Encouragingly, toxicological and behavioural studies revealed that mubritinib is well tolerated and spares normal cells. Our findings underscore the promising therapeutic potential of mubritinib, warranting its further exploration in clinic for glioblastoma therapy.

| S-SCDT-10_1038-S44321-025-00195-6 | biostudies-other

Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile.

Project description:Glioblastoma is one of the most treatment-resistant and lethal cancers, with a subset of self-renewing brain tumour stem cells (BTSCs), driving therapy resistance and relapse. Here, we report that mubritinib effectively impairs BTSC stemness and growth. Mechanistically, bioenergetic assays and rescue experiments showed that mubritinib targets complex I of the electron transport chain, thereby impairing BTSC self-renewal and proliferation. Gene expression profiling and Western blot analysis revealed that mubritinib disrupts the AMPK/p27Kip1 pathway, leading to cell-cycle impairment. By employing in vivo pharmacokinetic assays, we established that mubritinib crosses the blood-brain barrier. Using preclinical patient-derived and syngeneic models, we demonstrated that mubritinib delays glioblastoma progression and extends animal survival. Moreover, combining mubritinib with radiotherapy or chemotherapy offers survival advantage to animals. Notably, we showed that mubritinib alleviates hypoxia, thereby enhancing ROS generation, DNA damage, and apoptosis in tumours when combined with radiotherapy. Encouragingly, toxicological and behavioural studies revealed that mubritinib is well tolerated and spares normal cells. Our findings underscore the promising therapeutic potential of mubritinib, warranting its further exploration in clinic for glioblastoma therapy.

| S-EPMC11903783 | biostudies-literature

Quisinostat is a brain-penetrant radiosensitizer in glioblastoma

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

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Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib

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Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer’s disease proteopathology for precision medication

Project description:we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment.

2025-03-18 | PXD047045 | Pride

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

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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

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