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Shruti Bhargava - One of the best experts on this subject based on the ideXlab platform.

  • STEM-22. TARGETING PYRIMIDINE SYNTHESIS ACCENTUATES Molecular Therapy RESPONSE IN GLIOBLASTOMA STEM CELLS
    Neuro-Oncology, 2019
    Co-Authors: Kailin Yang, Xiuxing Wang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti Bhargava
    Abstract:

    Abstract 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 carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase (CAD) or the critical downstream enzyme, dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. 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 therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

  • Targeting pyrimidine synthesis accentuates Molecular Therapy response in glioblastoma stem cells.
    Science translational medicine, 2019
    Co-Authors: Xiuxing Wang, Kailin Yang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti Bhargava
    Abstract:

    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 carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. 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 in vitro. Higher expression of pyrimidine synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

Xiuxing Wang - One of the best experts on this subject based on the ideXlab platform.

  • STEM-22. TARGETING PYRIMIDINE SYNTHESIS ACCENTUATES Molecular Therapy RESPONSE IN GLIOBLASTOMA STEM CELLS
    Neuro-Oncology, 2019
    Co-Authors: Kailin Yang, Xiuxing Wang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti Bhargava
    Abstract:

    Abstract 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 carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase (CAD) or the critical downstream enzyme, dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. 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 therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

  • Targeting pyrimidine synthesis accentuates Molecular Therapy response in glioblastoma stem cells.
    Science translational medicine, 2019
    Co-Authors: Xiuxing Wang, Kailin Yang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti Bhargava
    Abstract:

    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 carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. 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 in vitro. Higher expression of pyrimidine synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

Kailin Yang - One of the best experts on this subject based on the ideXlab platform.

  • STEM-22. TARGETING PYRIMIDINE SYNTHESIS ACCENTUATES Molecular Therapy RESPONSE IN GLIOBLASTOMA STEM CELLS
    Neuro-Oncology, 2019
    Co-Authors: Kailin Yang, Xiuxing Wang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti Bhargava
    Abstract:

    Abstract 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 carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase (CAD) or the critical downstream enzyme, dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. 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 therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

  • Targeting pyrimidine synthesis accentuates Molecular Therapy response in glioblastoma stem cells.
    Science translational medicine, 2019
    Co-Authors: Xiuxing Wang, Kailin Yang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti Bhargava
    Abstract:

    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 carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. 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 in vitro. Higher expression of pyrimidine synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

Taro Shuin - One of the best experts on this subject based on the ideXlab platform.

  • hypoxia inducible protein 2 hig2 a novel diagnostic marker for renal cell carcinoma and potential target for Molecular Therapy
    The Journal of Urology, 2006
    Co-Authors: Akira Togashi, Toyomasa Katagiri, Shingo Ashida, Tomoaki Fujioka, Osamu Maruyama, Yoshiaki Wakumoto, Yoshiro Sakamoto, Makoto Fujime, Yoshio Kawachi, Taro Shuin
    Abstract:

    To identify molecules to serve as diagnostic markers for renal cell carcinoma (RCC) and as targets for novel therapeutic drugs, we investigated genome-wide expression profiles of RCCs using a cDNA microarray. We subsequently confirmed that hypoxia-inducible protein-2 (HIG2 )w as expressed exclusively in RCCs and fetal kidney. Induction of HIG2 cDNA into COS7 cells led to secretion of the gene product into culture medium and resulted in enhancement of cell growth. Small interfering RNA effectively inhibited expression of HIG2 in human RCC cells that endogenously expressed high levels of the protein and significantly suppressed cell growth. Moreover, addition of polyclonal anti-HIG2 antibody into culture medium induced apoptosis in RCC-derived cell lines. By binding to an extracellular domain of frizzled homologue 10 (FZD10), HIG2 protein enhanced oncogenic Wnt signaling and its own transcription, suggesting that this product is likely to function as an autocrine growth factor. ELISA analysis of clinical samples identified secretion of HIG2 protein into the plasma of RCC patients even at an early stage of tumor development, whereas it was detected at significantly lower levels in healthy volunteers or patients with chronic glomerulonephritis. The combined evidence suggests that this molecule represents a promising candidate for development of Molecular-targeting Therapy and could serve as a prominent diagnostic tumor marker for patients with renal carcinomas. (Cancer Res 2005; 65(11): 4817-26)

  • hypoxia inducible protein 2 hig2 a novel diagnostic marker for renal cell carcinoma and potential target for Molecular Therapy
    Cancer Research, 2005
    Co-Authors: Akira Togashi, Toyomasa Katagiri, Shingo Ashida, Tomoaki Fujioka, Osamu Maruyama, Yoshiaki Wakumoto, Yoshiro Sakamoto, Makoto Fujime, Yoshio Kawachi, Taro Shuin
    Abstract:

    To identify molecules to serve as diagnostic markers for renal cell carcinoma (RCC) and as targets for novel therapeutic drugs, we investigated genome-wide expression profiles of RCCs using a cDNA microarray. We subsequently confirmed that hypoxia-inducible protein-2 (HIG2) was expressed exclusively in RCCs and fetal kidney. Induction of HIG2 cDNA into COS7 cells led to secretion of the gene product into culture medium and resulted in enhancement of cell growth. Small interfering RNA effectively inhibited expression of HIG2 in human RCC cells that endogenously expressed high levels of the protein and significantly suppressed cell growth. Moreover, addition of polyclonal anti-HIG2 antibody into culture medium induced apoptosis in RCC-derived cell lines. By binding to an extracellular domain of frizzled homologue 10 (FZD10), HIG2 protein enhanced oncogenic Wnt signaling and its own transcription, suggesting that this product is likely to function as an autocrine growth factor. ELISA analysis of clinical samples identified secretion of HIG2 protein into the plasma of RCC patients even at an early stage of tumor development, whereas it was detected at significantly lower levels in healthy volunteers or patients with chronic glomerulonephritis. The combined evidence suggests that this molecule represents a promising candidate for development of Molecular-targeting Therapy and could serve as a prominent diagnostic tumor marker for patients with renal carcinomas.

Yu Shi - One of the best experts on this subject based on the ideXlab platform.

  • STEM-22. TARGETING PYRIMIDINE SYNTHESIS ACCENTUATES Molecular Therapy RESPONSE IN GLIOBLASTOMA STEM CELLS
    Neuro-Oncology, 2019
    Co-Authors: Kailin Yang, Xiuxing Wang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti Bhargava
    Abstract:

    Abstract 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 carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase (CAD) or the critical downstream enzyme, dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. 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 therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

  • Targeting pyrimidine synthesis accentuates Molecular Therapy response in glioblastoma stem cells.
    Science translational medicine, 2019
    Co-Authors: Xiuxing Wang, Kailin Yang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti Bhargava
    Abstract:

    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 carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. 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 in vitro. Higher expression of pyrimidine synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.