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Venetoclax cooperates with ionizing radiation to attenuate Diffuse Midline Glioma tumor growth

ABSTRACT: This article highlights the radiation induced cytotoxic effect of the BCL2 inhibitor, venetoclax, in diffuse midline gliomas (DMG). 1. RNA-seq: We performed bulk RNA sequencing of DMG cells exposed to 6Gy radiation and found the genes upregulated after radiation compared to unirradiated controls. 2. DNA Repair shRNA screen: We also performed a DNA Repair shRNA screen and identified the genes which are responsible for radioresistance in DMG.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198979 | GEO | 2022/03/23

REPOSITORIES: GEO

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Ataxia-telangiectasia mutated (Atm) disruption sensitizes spatially-directed H3.3K27M/TP53 diffuse midline gliomas to radiation therapy

Project description:Diffuse midline gliomas (DMGs) are lethal brain tumors characterized by inactivating p53 mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress, presenting therapeutic opportunities. We used RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce K27M in the native H3f3a allele in a lineage- and spatially-directed manner, yielding primary mouse DMGs. Disruption of the DNA damage response kinase Ataxia-telangiectasia mutated (Atm) enhanced the efficacy of focal brain irradiation, extending mouse survival. This finding suggests that targeting ATM will enhance the efficacy of radiation therapy for p53-mutant DMG but not p53-wildtype DMG. We used spatial in situ transcriptomics and an allelic series of primary murine DMG models to identify transactivation-independent p53 activity as the key mediator of such radiosensitivity.

2023-11-04 | GSE246584 | GEO

Venetoclax cooperates with ionizing radiation to attenuate Diffuse Midline Glioma tumor growth

Project description:Venetoclax cooperates with ionizing radiation to attenuate Diffuse Midline Glioma tumor growth

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Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation

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Therapeutic opportunities for diffuse midline glioma identified from high-throughput combination drug screening

Project description:Diffuse midline gliomas (DMG) are a group of molecularly related malignancies occurring in midline structures of the childhood central nervous system, including thalamus, pons, and spinal cord. These cancers are characterized by high prevalence of the histone-3K27M mutation and are universally lethal, with median survival of only 9-11 months for pontine DMG (a.k.a. DIPG). In search of novel therapeutic options, we examined multiple cell models in sequential, quantitative high-throughput screens of approved and investigational drugs. This effort generated a total of 17,456 single-agent dose responses that inspired a subsequent series of HTS-enabled drug combination assessments encompassing a total of 8883 drug-drug examinations. Top combinations were validated across a panel of patient-derived cell lines representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-HDAC inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to the cellular unfolded protein response and key metabolic processes following treatment with panobinostat and marizomib. Rescue of drug induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking NAD+ production via NAMPT inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study represents the most comprehensive single-agent and combinatorial drug screen for DIPG reported to date and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores under-recognized metabolic vulnerabilities in DIPG. The combined screening outcomes represent a public resource for the DMG community.

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Integrated analyses reveal two molecularly and clinically distinct subtypes of H3 K27M-mutant diffuse midline gliomas with prognostic significance

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Preclinical Optimization of the PI3K/Akt inhibitor Paxalisib for the Treatment of Diffuse Midline Glioma

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Unirradiated HCT116-CloneK cells

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ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma

Project description:Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.

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Multi-omics approaches reveal that Diffuse Midline Gliomas are susceptible to replication stress therapy and cholesterol biosynthesis inhibition [Repli-seq]

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