The Experts below are selected from a list of 7980 Experts worldwide ranked by ideXlab platform
Hsing Jien Kung - One of the best experts on this subject based on the ideXlab platform.
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Abstract A171: Targeting Tumor Metabolism by novel EGFR inhibitor in head and neck cancer
Molecular Cancer Therapeutics, 2020Co-Authors: Hsing-pang Hsieh, Hsing Jien KungAbstract:Cellular Metabolism is substantially altered during Tumor progression, and associated with poor prognosis and therapeutic resistance of human cancers. Therefore, the metabolic rewiring of cancer cells has been viewed as a promising source for novel drug targets, and being actively pursued in the development of selective antineoplastic agents. EGFR targeted agents currently approved or under investigation for head and neck squamous cell carcinoma (HNSCC) include EGFR monoclonal antibodies or EGFR tyrosine kinase inhibitors (EGFR-TKI). However, HNSCC patients failing to these agents treatment, due to the development of acquired Tumor resistance, will have a compromised survival. We have identified a novel EGFR-TKI, BPR3K007S0. Based on the EC50 in enzyme-based assay of wild-type EGFR & EGFR mutant L858R protein, BPR3K007S0 is more effective than that of clinical used EGFR-TKI gefitinib (Iressa). We further evaluated the drug effects on EGFR phosphorylation in HNSCC cells, and found that BPR3K007S0 inhibited phosphorylation of EGFR in a time-dependent manner. Further study demonstrated that BPR3K007S0 decreased HNSCC cell proliferation and colony formation by causing G1-phase arrest, which was strongly associated with a marked decrease of the level of cyclin E and cdk2 with concomitant induction of p21 and p27. Notably, BPR3K007S0 showed much potent effect toward cell growth in vitro and in vivo than that of gefitinib in HNSCC cells, implicating that the anticancer effect of BPR3K007S0 is not limited to EGFR inhibition. More importantly, we found that BPR3K007S0 significantly suppressed the expression of a wide range of metabolic genes. Among them, the levels of c-Myc and hexokinase 2 were significantly decreased in a time-dependent manner by treatment with BPR3K007S0. Gene manipulation study demonstrated that knockdown of c-Myc leads to a decreased level of hexokinase 2. In this system, silence of EGFR did not affect c-Myc expression, suggesting that c-Myc may not be the EGFR downstream target in used HNSCC cells. Taken together, these results revealed that BPR3K007S0 has added benefits by targeting of EGFR and cancer Metabolism, and are likely to be superior to gefitinib in HNSCC models. Thus, development of multi-kinase and metabolic inhibitors holds promises for overcoming treatment resistance of HNSCC. (Grant support: DOH102-TD-M-111-102001) Citation Format: Ching-Chuan Kuo, Hsing-Pang Hsieh, Hsing-Jien Kung. Targeting Tumor Metabolism by novel EGFR inhibitor in head and neck cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A171.
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Abstract 3944: Blockage of EGFR signaling repurposes Tumor Metabolism through suppression of glycolysis and Kreb cycle in head and neck cancer
Cancer Research, 2018Co-Authors: Jang Yang Chang, Hsing Jien Kung, Hsing-pang Hsieh, Hsih-huei Chang, Chih-hsiang Huang, Yi-yu KeAbstract:Head and neck squamous cell carcinoma (HNSCC), the most common malignant neoplasm arising in the mucosa of the upper aerodigestive tract, remains a significant cause of morbidity worldwide. With respect to the cancer treatment, HNSCC has a moderately good survival rate, however, the disease often recurs, leading to a poor prognostic disease course and tends to fail in treatment. The metabolic properties of cancer cells diverge significantly from those of normal cells. Emerging evidence suggests these metabolic alterations are also linked to therapeutic resistance in cancer treatment. EGFR targeted agents currently approved or under investigation for HNSCC. We recently identified a novel EGFR tyrosine kinase inhibitor (EGFR-TKI), BPR3K007S0, and found that this compound significantly inhibited EGFR phosphorylation in EGFR-overexpressing HNSCC cells in vitro and in vivo than that of gefitinib. BPR3K007S0 significantly suppressed the expression of a wide range of metabolic genes, including metabolic-related transcription factors, glycolysis, TCA cycle, and pentose phosphate pathway genes. Collectively, we also found that BPR3K007S0 significantly decreased glycolytic and mitochondria respiratory capacity. Pharmacological and genetic manipulation demonstrated that c-Myc/hexokinase 2 axis was one of downstream effector in response to EGFR inhibition. Furthermore, we found that EGFR-TKIs were able to suppress succinate dehydrogenase A leading to reduce fumarate, an oncometabolite generates from Kreb cycle, and contributed to EGFR-TKIs mediated antiTumor effect. Taken together, these results revealed that blockage of EGFR signaling repurposes Tumor Metabolism through suppression of hexokinase 2 and succinate dehydrogenase A, in glycolysis and Kreb cycle, respectively, and demonstrated added benefits to treatment of HNSCCs. Citation Format: Ching-Chuan Kuo, Jang-Yang Chang, Hsing-Pang Hsieh, Hsing-Jien Kung, Hsih-Huei Chang, Chih-Hsiang Huang, Cheng-Chin Kuo, Yi-Yu Ke. Blockage of EGFR signaling repurposes Tumor Metabolism through suppression of glycolysis and Kreb cycle in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3944.
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Abstract B16: A novel long non-coding RNA connects c-Myc to Tumor Metabolism
Molecular Cancer Research, 2015Co-Authors: Ling Yu Wang, Chiu-lien Hung, Yen-ling Yu, Hongwu Chen, Shiv Srivastava, Gyorgy Petrovics, Hsing Jien KungAbstract:Long non-coding RNAs have been implicated in a variety of physiological and pathological processes including cancer. In prostate cancer, PCGEM1 (prostate cancer gene expression marker 1) is an androgen-induced prostate specific lncRNA whose overexpression is highly associated with prostate Tumors. PCGEM19s Tumorigenic potential was recently shown to be in part due to its ability to activate androgen receptor (AR). Here we report a novel function of PCGEM1 that provides growth advantages for cancer cell by regulating Tumor Metabolism via c-Myc activation. PCGEM1 promotes glucose uptake for aerobic glycolysis, coupling with pentose phosphate shunt to facilitate biosynthesis of nucleotide and lipid, and generates NADPH for redox homeostasis. We show that PCGEM1 regulates Metabolism at the transcriptional level that affects multiple metabolic pathways including glucose and glutamine Metabolism, pentose phosphate pathway, nucleotide and fatty acid biosynthesis, and TCA cycle. The PCGEM1-mediated gene regulation takes place in part through AR activation, but predominantly through c-Myc activation regardless of hormone or AR status. Significantly, PCGEM1 binds directly to target promoters, physically interacts with c-Myc, promotes chromatin recruitment of c-Myc, and enhances its transactivation activity. We also identified c-Myc binding domain on PCGEM1 that contributes to the PCGEM1 dependent c-Myc activation and target induction. Together, our data uncover PCGEM1 as a key transcriptional regulator of central metabolic pathways in prostate cancer cell. By being a coactivator for both c-Myc and AR, PCGEM1 reprograms the androgen network and the central Metabolism in a Tumor specific way, making it a promising target for therapeutic intervention. Citation Format: Ling-Yu Wang, Chiu-Lien Hung, Yen-Ling Yu, Hongwu Chen, Shiv Srivastava, Gyorgy Petrovics, Hsing-Jien Kung. A novel long non-coding RNA connects c-Myc to Tumor Metabolism. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B16.
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a long noncoding rna connects c myc to Tumor Metabolism
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Chiu-lien Hung, Ling Yu Wang, Yen-ling Yu, Hongwu Chen, Shiv Srivastava, Gyorgy Petrovics, Hsing Jien KungAbstract:Long noncoding RNAs (lncRNAs) have been implicated in a variety of physiological and pathological processes, including cancer. In prostate cancer, prostate cancer gene expression marker 1 (PCGEM1) is an androgen-induced prostate-specific lncRNA whose overexpression is highly associated with prostate Tumors. PCGEM1’s Tumorigenic potential has been recently shown to be in part due to its ability to activate androgen receptor (AR). Here, we report a novel function of PCGEM1 that provides growth advantages for cancer cells by regulating Tumor Metabolism via c-Myc activation. PCGEM1 promotes glucose uptake for aerobic glycolysis, coupling with the pentose phosphate shunt to facilitate biosynthesis of nucleotide and lipid, and generates NADPH for redox homeostasis. We show that PCGEM1 regulates Metabolism at a transcriptional level that affects multiple metabolic pathways, including glucose and glutamine Metabolism, the pentose phosphate pathway, nucleotide and fatty acid biosynthesis, and the tricarboxylic acid cycle. The PCGEM1-mediated gene regulation takes place in part through AR activation, but predominantly through c-Myc activation, regardless of hormone or AR status. Significantly, PCGEM1 binds directly to target promoters, physically interacts with c-Myc, promotes chromatin recruitment of c-Myc, and enhances its transactivation activity. We also identified a c-Myc binding domain on PCGEM1 that contributes to the PCGEM1-dependent c-Myc activation and target induction. Together, our data uncover PCGEM1 as a key transcriptional regulator of central metabolic pathways in prostate cancer cells. By being a coactivator for both c-Myc and AR, PCGEM1 reprograms the androgen network and the central Metabolism in a Tumor-specific way, making it a promising target for therapeutic intervention.
Eileen White - One of the best experts on this subject based on the ideXlab platform.
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autophagy and Tumor Metabolism
Cell Metabolism, 2017Co-Authors: Alec C Kimmelman, Eileen WhiteAbstract:Autophagy is a critical cellular process that generally protects cells and organisms from stressors such as nutrient deprivation. In addition to its role in normal physiology, autophagy plays a role in pathological processes such as cancer. Indeed, there has been substantial work exploring the complex and context-dependent role of autophagy in cancer. One of the emerging themes is that in certain cancer types, autophagy is important to support Tumor growth; therefore, inhibiting autophagy as a therapeutic approach is actively being tested in clinical trials. A key mechanism of how autophagy promotes the growth and survival of various cancers is its ability to support cellular Metabolism. The diverse metabolic fuel sources that can be produced by autophagy provide Tumors with metabolic plasticity and can allow them to thrive in what can be an austere microenvironment. Therefore, understanding how autophagy can fuel cellular Metabolism will enable more effective combinatorial therapeutic strategies.
Renaud De Crevoisier - One of the best experts on this subject based on the ideXlab platform.
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EMBC - Weighted quantification of 18 F-FDG Tumor Metabolism activity using fuzzy-thresholding to predict post-treatment Tumor recurrence
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and, 2015Co-Authors: Geoffrey Roman-jimenez, Oscar Acosta, Julie Leseur, Anne Devillers, Jonathan Le Gouestre, Juan-david Ospina, Antoine Simon, Pierre Terve, Renaud De CrevoisierAbstract:Cervical cancer is one of the most common cancer to affect women worldwide. Despite the efficiency of radiotherapy treatment, some patients present post-treatment Tumor recurrence which increases the risk of death. Early outcome prediction could help oncologists to adapt the treatment. Several studies suggest that quantification of Tumor activity using (18)FFDG PET imaging could be used to predict post-treatment Tumor recurrence. In this paper we study the predictive value of weighted quantification of Tumor Metabolism extracted by fuzzy-thresholding for Tumor recurrence of locally advanced cervical cancer. Fifty-three patients with locally advanced cervical cancer treated by chemo-radiotherapy were considered in our study. For each patient, a coregistered (18)F-FDG PET/CT scan was acquired before the treatment and was segmented using different hard and fuzzy segmentations methods. The Tumor activity was extracted through the total lesion glycolysis and through a weighted analog of the total lesion glycolysis using the probability maps provided by the fuzzy segmentations. Outcomes prediction was performed using the area under the receiver operating characteristic curve (AUC) and the Harrell's C-index. Results suggest that weighted quantification of Tumor activity seems to be strongly informative and could be used to predict post-treatment Tumor recurrence in cervical cancer.
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Weighted quantification of 18F-FDG Tumor Metabolism activity using fuzzy-thresholding to predict post-treatment Tumor recurrence
2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 2015Co-Authors: Geoffrey Roman-jimenez, Oscar Acosta, Julie Leseur, Anne Devillers, Jonathan Le Gouestre, Juan-david Ospina, Antoine Simon, Pierre Terve, Renaud De CrevoisierAbstract:Cervical cancer is one of the most common cancer to affect women worldwide. Despite the efficiency of radiotherapy treatment, some patients present post-treatment Tumor recurrence which increases the risk of death. Early outcome prediction could help oncologists to adapt the treatment. Several studies suggest that quantification of Tumor activity using 18FFDG PET imaging could be used to predict post-treatment Tumor recurrence. In this paper we study the predictive value of weighted quantification of Tumor Metabolism extracted by fuzzy-thresholding for Tumor recurrence of locally advanced cervical cancer. Fifty-three patients with locally advanced cervical cancer treated by chemo-radiotherapy were considered in our study. For each patient, a coregistered 18F-FDG PET/CT scan was acquired before the treatment and was segmented using different hard and fuzzy segmentations methods. The Tumor activity was extracted through the total lesion glycolysis and through a weighted analog of the total lesion glycolysis using the probability maps provided by the fuzzy segmentations. Outcomes prediction was performed using the area under the receiver operating characteristic curve (AUC) and the Harrell's C-index. Results suggest that weighted quantification of Tumor activity seems to be strongly informative and could be used to predict post-treatment Tumor recurrence in cervical cancer.
Michael P Lisanti - One of the best experts on this subject based on the ideXlab platform.
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two compartment Tumor Metabolism autophagy in the Tumor microenvironment and oxidative mitochondrial Metabolism oxphos in cancer cells
Cell Cycle, 2012Co-Authors: Ahmed F Salem, Diana Whitakermenezes, Ubaldo E Martinezoutschoorn, Herbert B Tanowitz, Mazhar Alzoubi, Anthony Howell, Richard G Pestell, Federica Sotgia, Michael P LisantiAbstract:Previously, we proposed a new paradigm to explain the compartment-specific role of autophagy in Tumor Metabolism. In this model, autophagy and mitochondrial dysfunction in the Tumor stroma promotes cellular catabolism, which results in the production of recycled nutrients. These chemical building blocks and high-energy “fuels” would then drive the anabolic growth of Tumors, via autophagy resistance and oxidative mitochondrial Metabolism in cancer cells. We have termed this new form of stromal-epithelial metabolic coupling: “two-compartment Tumor Metabolism.” Here, we stringently tested this energy-transfer hypothesis, by genetically creating (1) constitutively autophagic fibroblasts, with mitochondrial dysfunction or (2) autophagy-resistant cancer cells, with increased mitochondrial function. Autophagic fibroblasts were generated by stably overexpressing key target genes that lead to AMP-kinase activation, such as DRAM and LKB1. Autophagy-resistant cancer cells were derived by overexpressing GOLPH3, which...
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Two-compartment Tumor Metabolism: Autophagy in the Tumor microenvironment and oxidative mitochondrial Metabolism (OXPHOS) in cancer cells
Cell Cycle, 2012Co-Authors: Ahmed F Salem, Herbert B Tanowitz, Anthony Howell, Richard G Pestell, Federica Sotgia, Diana Whitaker-menezes, Ubaldo E. Martinez-outschoorn, Mazhar Al-zoubi, Michael P LisantiAbstract:Previously, we proposed a new paradigm to explain the compartment-specific role of autophagy in Tumor Metabolism. In this model, autophagy and mitochondrial dysfunction in the Tumor stroma promotes cellular catabolism, which results in the production of recycled nutrients. These chemical building blocks and high-energy "fuels" would then drive the anabolic growth of Tumors, via autophagy resistance and oxidative mitochondrial Metabolism in cancer cells. We have termed this new form of stromal-epithelial metabolic coupling: "two-compartment Tumor Metabolism." Here, we stringently tested this energy-transfer hypothesis, by genetically creating (1) constitutively autophagic fibroblasts, with mitochondrial dysfunction or (2) autophagy-resistant cancer cells, with increased mitochondrial function. Autophagic fibroblasts were generated by stably overexpressing key target genes that lead to AMP-kinase activation, such as DRAM and LKB1. Autophagy-resistant cancer cells were derived by overexpressing GOLPH3, which functionally promotes mitochondrial biogenesis. As predicted, DRAM and LKB1 overexpressing fibroblasts were constitutively autophagic and effectively promoted Tumor growth. We validated that autophagic fibroblasts showed mitochondrial dysfunction, with increased production of mitochondrial fuels (L-lactate and ketone body accumulation). Conversely, GOLPH3 overexpressing breast cancer cells were autophagy-resistant, and showed signs of increased mitochondrial biogenesis and function, which resulted in increased Tumor growth. Thus, autophagy in the Tumor stroma and oxidative mitochondrial Metabolism (OXPHOS) in cancer cells can both dramatically promote Tumor growth, independently of Tumor angiogenesis. For the first time, our current studies also link the DNA damage response in the Tumor microenvironment with "Warburg-like" cancer Metabolism, as DRAM is a DNA damage/repair target gene.
Wolfgang A Weber - One of the best experts on this subject based on the ideXlab platform.
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changes in Tumor Metabolism as readout for mammalian target of rapamycin kinase inhibition by rapamycin in glioblastoma
Clinical Cancer Research, 2008Co-Authors: Helen Su, Isabel Hildebrandt, Michael E Phelps, Johannes Czernin, Wolfgang A WeberAbstract:Purpose: Inhibition of the protein kinase mammalian target of rapamycin (mTOR) is being evaluated for treatment of a variety of malignancies. However, the effects of mTOR inhibitors are cytostatic and standard size criteria do not reliably identify responding Tumors. The aim of this study was to evaluate whether response to mTOR inhibition could be assessed by positron emission tomography (PET) imaging of Tumor Metabolism. Experiment Design: Glucose, thymidine, and amino acid utilization of human glioma cell lines with varying degrees of sensitivity to mTOR inhibition were assessed by measuring in vitro uptake of [ 18 F]fluorodeoxyglucose ([ 18 F]FDG), [ 18 F]fluorothymidine ([ 18 F]FLT), and [ 3 H]l-tyrosine before and after treatment with the mTOR inhibitor rapamycin. The Tumor metabolic activity in vivo was monitored by small-animal PET of Tumor-bearing mice. The mechanisms underlying changes in metabolic activity were analyzed by measuring expression and functional activity of enzymes and transporters involved in the uptake of the studied imaging probes. Results: In sensitive cell lines, rapamycin decreased [ 18 F]FDG and [ 18 F]FLT uptake by up to 65% within 24 hours after the start of therapy. This was associated with inhibition of hexokinase and thymidine kinase 1. In contrast, [ 3 H]l-tyrosine uptake was unaffected by rapamycin. The effects of rapamycin on glucose and thymidine Metabolism could be imaged noninvasively by PET. In sensitive Tumors, [ 18 F]FDG and [ 18 F]FLT uptake decreased within 48 hours by 56 ± 6% and 52 ± 8%, respectively, whereas there was no change in rapamycin-resistant Tumors. Conclusions: These encouraging preclinical data warrant clinical trials evaluating [ 18 F]FDG and [ 18 F]FLT-PET for monitoring treatment with mTOR inhibitors in patients.
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quantitative assessment of Tumor Metabolism using fdg pet imaging
Nuclear Medicine and Biology, 2000Co-Authors: Wolfgang A Weber, Markus Schwaiger, Norbert AvrilAbstract:Abstract Positron emission tomography using the glucose analog fluorine-18 fluorodeoxyglucose (FDG-PET) provides a unique means of non-invasive assessment of Tumor Metabolism. Several approaches, of varying complexity, can be applied for quantitative image analysis. Previous studies have demonstrated that “standardized uptake values” (SUV) and simplified tracer kinetic modeling, using the “Patlak-Gjedde”-analysis, provide highly reproducible parameters of Tumor glucose utilization. Quantification of regional FDG uptake gives complementary information to visual image interpretation and provides objective criteria for differentiation between benign and malignant lesions. Moreover, quantification of Tumor glucose Metabolism is essential for assessment of therapy induced changes. Clinical studies in breast cancer and lymphoma suggest that serial FDG-PET studies allow the prediction of response early in the course of chemotherapy. Therefore, FDG-PET may be helpful in patient management by avoiding ineffective chemotherapy and supporting the decision to continue dose intense regimes. In addition, FDG-PET allows non-invasive assessment of Tumor viability following chemo- and radiotherapy which permits individualized therapy management.
