Novel Targeting of Transcription and Metabolism in Glioblastoma
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ABSTRACT:
PROVIDER: PRJNA420677 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR6337810_1.fastq.gz | Fastqsanger.gz | |||
| SRR6337810_2.fastq.gz | Fastqsanger.gz | |||
| SRR6337811_1.fastq.gz | Fastqsanger.gz | |||
| SRR6337811_2.fastq.gz | Fastqsanger.gz | |||
| SRR6337812_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Glioblastoma (GBM) is highly resistant to treatment, largely due to disease heterogeneity and resistance mechanisms. We sought to investigate a promising drug that can inhibit multiple aspects of cancer cell survival mechanisms and become effective therapeutics for GBM patients. Experimental Design: To investigate TG02, an agent with known penetration of the Blood-Brain Barrier, we examined the effects as single agent and in combination with temozolomide, a commonly used chemotherapy in GBM. We utilized human GBM cells and a syngeneic mouse orthotopic GBM model, evaluating survival and the pharmacodynamics of TG02. Mechanistic studies included TG02-induced transcriptional regulation, apoptosis and RNA sequencing in treated GBM cells as well as the investigation of mitochondrial and glycolytic function assays. Results: We demonstrated that TG02 inhibited cell proliferation, induced cell death, and synergized with temozolomide in GBM cells with different genetic background but not in astrocytes. TG02-induced cytotoxicity was blocked by the overexpression of phosphorylated CDK9, suggesting a CDK9-dependent cell killing. TG02 suppressed transcriptional progression of anti-apoptotic proteins, and induced apoptosis in GBM cells. We further demonstrated that TG02 caused mitochondrial dysfunction and glycolytic suppression and ultimately ATP depletion in GBM. A prolonged survival was observed in GBM mice receiving combined treatment of TG02 and temozolomide. The TG02-induced decrease of CDK9 phosphorylation was confirmed in the brain tumor tissue. Conclusions: TG02 inhibits multiple survival mechanisms and synergistically decreases energy production with temozolomide, representing a promising therapeutic strategy in GBM, currently under investigation in an ongoing clinical trial.
2017-12-02 | GSE107601 | GEO
Project description:Purpose: Glioblastoma (GBM) is highly resistant to treatment, largely due to disease heterogeneity and resistance mechanisms. We sought to investigate a promising drug that can inhibit multiple aspects of cancer cell survival mechanisms and become an effective therapeutic for GBM patients.Experimental Design: To investigate TG02, an agent with known penetration of the blood-brain barrier, we examined the effects as single agent and in combination with temozolomide, a commonly used chemotherapy in GBM. We used human GBM cells and a syngeneic mouse orthotopic GBM model, evaluating survival and the pharmacodynamics of TG02. Mechanistic studies included TG02-induced transcriptional regulation, apoptosis, and RNA sequencing in treated GBM cells as well as the investigation of mitochondrial and glycolytic function assays.Results: We demonstrated that TG02 inhibited cell proliferation, induced cell death, and synergized with temozolomide in GBM cells with different genetic background but not in astrocytes. TG02-induced cytotoxicity was blocked by the overexpression of phosphorylated CDK9, suggesting a CDK9-dependent cell killing. TG02 suppressed transcriptional progression of antiapoptotic proteins and induced apoptosis in GBM cells. We further demonstrated that TG02 caused mitochondrial dysfunction and glycolytic suppression and ultimately ATP depletion in GBM. A prolonged survival was observed in GBM mice receiving combined treatment of TG02 and temozolomide. The TG02-induced decrease of CDK9 phosphorylation was confirmed in the brain tumor tissue.Conclusions: TG02 inhibits multiple survival mechanisms and synergistically decreases energy production with temozolomide, representing a promising therapeutic strategy in GBM, currently under investigation in an ongoing clinical trial. Clin Cancer Res; 24(5); 1124-37. ©2017 AACR.
| S-EPMC8108069 | biostudies-literature
Project description:Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase) or the critical downstream enzyme, DHODH (dihydroorotate dehydrogenase) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity. Higher expression of pyrimidine synthesis genes portend poor prognosis of glioblastoma patients. Collectively, our results demonstrate a novel therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.
2019-04-09 | GSE129438 | GEO
Project description:Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSCs). Here, we show that GSCs, differentiated glioblastoma cells (DGCs), and normal brain cultures all displayed robust circadian rhythms, yet GSCs alone displayed exquisite dependence on core clock transcription factors, BMAL1 and CLOCK, for optimal cell growth. Downregulation of BMAL1 or CLOCK in GSCs induced cell cycle arrest and apoptosis. Chromatin immunoprecipitation revealed BMAL1 preferentially bound at metabolic genes in GSCs, associated with differences in active chromatin regions compared to NSCs. Targeting BMAL1 or CLOCK attenuated mitochondrial metabolic function and reduced expression of the tricarboxylic acid (TCA) cycle enzymes. Small molecule agonists of two independent BMAL1::CLOCK negative regulators, the Cryptochromes and REV-ERBs, downregulated stem cell factors and reduced GSC growth. Combination of Cryptochrome and REV-ERB agonists induced synergistic anti-tumor efficacy. Collectively, GSCs coopt circadian regulators beyond canonical circadian circuitry to promote stemness maintenance and metabolism, offering novel therapeutic paradigms.
2019-10-24 | GSE134973 | GEO
Project description:Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSCs). Here, we show that GSCs, differentiated glioblastoma cells (DGCs), and normal brain cultures all displayed robust circadian rhythms, yet GSCs alone displayed exquisite dependence on core clock transcription factors, BMAL1 and CLOCK, for optimal cell growth. Downregulation of BMAL1 or CLOCK in GSCs induced cell cycle arrest and apoptosis. Chromatin immunoprecipitation revealed BMAL1 preferentially bound at metabolic genes in GSCs, associated with differences in active chromatin regions compared to NSCs. Targeting BMAL1 or CLOCK attenuated mitochondrial metabolic function and reduced expression of the tricarboxylic acid (TCA) cycle enzymes. Small molecule agonists of two independent BMAL1::CLOCK negative regulators, the Cryptochromes and REV-ERBs, downregulated stem cell factors and reduced GSC growth. Combination of Cryptochrome and REV-ERB agonists induced synergistic anti-tumor efficacy. Collectively, GSCs coopt circadian regulators beyond canonical circadian circuitry to promote stemness maintenance and metabolism, offering novel therapeutic paradigms.
2019-10-24 | GSE134972 | GEO
Project description:Identification of novel transcription factors that regulate prostate cancer cell metabolism
| PRJNA635396 | ENA
Project description:Abstract BACKGROUND Glioblastoma (GBM), a common malignant brain tumor, is highly resistant to most treatments, largely due to disease heterogeneity and resistance mechanisms. We investigated TG02, a multi-kinase inhibitor with established anti-tumor activities in hematologic malignancies, for a potential GBM therapy. We previously demonstrated that TG02 inhibited CDK9-mediated transcriptional regulation of anti-apoptotic proteins and induced Cytochrome c release, inducing cell apoptosis through Caspase-3 activation. Additionally, TG02 and Temozolomide (TMZ) demonstrated a synergistic anti-glioma effect in vivo and in vitro. METHODS A phosphorylation mimic form of CDK9 was overexpressed in GBM cell and cell viability was via cell counting. NADH dehydrogenase activity was measured to determine mitochondrial respiratory chain complex I activity. The glycolytic effects were measured by Seahorse assay and Western blotting of the key enzymes. Mitochondrial membrane potential change and apoptosis were measured by FACS with DiOC6, and Hoechst/PI staining, respectively. Pharmacodynamic studies were carried out using a syngeneic GBM mouse model. RESULTS We demonstrated that overexpressed phosphorylation mimic form of CDK9 partially blocked TG02-induced cell death, suggesting that CDK9 mediates TG02-induced cytotoxicity. We demonstrated that TG02 caused mitochondrial dysfunction partially by reducing mitochondrial respiratory chain complex I activity. Additionally, TG02 inhibited glycolysis by downregulating key glycolytic regulators, including Hexokinase-2 (HK-2) and Pyruvate kinase M2 (PKM2), leading to ATP depletion. Combined treatment further enhanced ATP depletion, explaining the synergism between TG02 and TMZ. More importantly, TG02 did not cause mitochondrial damage and apoptosis in normal human astrocytes, suggesting a feasible therapeutic window for TG02. Furthermore, our pharmacodynamic studies confirmed that TG02 suppressed CDK9 activity in brain tumor tissues. CONCLUSIONS TG02 has unique anti-glioma effects through transcriptional regulation of survival proteins, and reduction of cellular energy level in GBM cells. Our preclinical results have led to an ongoing Phase I//II clinical trial for patients with refractory GBM (NCT02942264).
| S-EPMC5693086 | biostudies-literature
Project description:Achievement of specific tumor cell targeting remains a challenge for glioma gene therapy. We report here the identification and characterization of a 5’ sequence of human HMGB2 gene for transcriptional targeting to glioblastoma. We performed microarray analysis and found HMGB2 as one of the genes that had a low level of expression in normal human astrocytes, but was significantly up-regulated in glioblastoma cells. Real-time PCR quantification revealed increase in HMBG2 expression level in glioblastoma tissues and cells between 11 to 79 fold over that in normal human brain tissue. With progressive truncation of a 5’-upstream sequence of the HMGB2 gene, we identified a 500-bp fragment that displayed a high transcriptional activity in glioblastoma cells, but a low activity in normal brain cells. Using the sequence to drive the expression of the herpes simplex virus thymidine kinase gene in the context of a baculoviral vector, glioblastoma cells died in the presence of ganciclovir, whereas normal human astrocytes and neurons were not affected. We further confirmed that after intra-tumor injection, the baculoviral vector effectively suppressed the growth of human glioblastoma cells in a mouse xenograft model. Our results suggest that the 5’-upstream sequence of the HMGB2 gene can be used as an efficient, tumor-selective promoter in targeted vectors for glioblastoma gene therapy. U251 cells (n=3) genes level expression were compared to that of normal astrocytes (n=3) to find overexpressed genes in glioblastoma. Highly expressed genes were compared to those found in the litterature. This was selected to clone promoters of highly expressed genes in glioblastomas
2008-12-31 | E-GEOD-12305 | biostudies-arrayexpress
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Project description:Glioblastoma ranks among the most lethal of primary brain malignancies, with glioblastoma stem cells (GSCs) at the apex of tumor cellular hierarchies. Here, to discover novel therapeutic GSC targets, we interrogated gene expression profiles from GSCs, differentiated glioblastoma cells (DGCs), and neural stem cells (NSCs), revealing EYA2 as preferentially expressed by GSCs. Targeting EYA2 impaired GSC maintenance and induced cell cycle arrest, apoptosis, and loss of self-renewal. EYA2 displayed novel localization to centrosomes in GSCs, and EYA2 tyrosine (Tyr) phosphatase activity was essential for proper mitotic spindle assembly and survival of GSCs. Inhibition of the EYA2 Tyr phosphatase activity, via genetic or pharmacological means, mimicked EYA2 loss in GSCs in vitro and extended the survival of tumor-bearing mice. Supporting the clinical relevance of these findings, EYA2 portends poor patient prognosis in glioblastoma. Collectively, our data indicate that EYA2 phosphatase function plays selective critical roles in the growth and survival of GSCs, potentially offering a high therapeutic index for EYA2 inhibitors.
2021-09-25 | GSE135306 | GEO