The Experts below are selected from a list of 36417 Experts worldwide ranked by ideXlab platform
Frederick L Hall - One of the best experts on this subject based on the ideXlab platform.
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Abstract 2556: Enhanced expression of human Cyclin G1 (CCNG1) gene in metastatic cancer, a novel biomarker in development for CCNG1 inhibitor therapy
Molecular and Cellular Biology Genetics, 2019Co-Authors: Erlinda M Gordon, Joshua Ravicz, Sant P Chawla, Michael A. Morse, Christopher Szeto, Sandeep K. Reddy, Frederick L HallAbstract:Background: Metastatic cancer is associated with, hitherto, an invariably fatal outcome. DeltaRex-G, a CCNG1 inhibitor, has induced long term (9-12 year-) survivorship in patients with metastatic melanoma, sarcoma, lymphoma and cancer of pancreas and breast. Purpose: To evaluate CCNG1 expression in tumors as a novel biomarker for identification of patients who are likely to benefit from CCNG1 inhibitor therapy. Methods: RNA sequence analysis was used to compare CCNG1 expression in tumor (TCGA, N=9161) versus normal tissues (TGCA, N=678 and GTEx, N=7187) from 20 organ sites, and in primary vs metastatic melanoma (N=106 & 367 respectively). Using IHC staining, the significance of differences between the number of CCNG1+ and Ki-67+ cells in normal tissues vs tumors were evaluated using paired Student’s t test. Pearson’s coefficient of correlation was used to evaluate the relationship between the number of Ki-67+ vs CCNG1+ cells. Results: CCNG1 gene expression, by RNA sequence analysis, was significantly enhanced in melanoma, sarcoma, leukemia, and cancers of the lung, thyroid, brain, liver, prostate, testicle, head and neck, bladder, kidney, adrenal, cervix, and pancreas, compared to normal tissues (p = 0.006- 1.8E-58), and even greater, in metastatic vs primary melanoma. In a subset of melanoma tumors, there was overall positive correlation with progression/metastasis in both Ki67 and CCNG1 expression levels. Consistent with these findings, IHC showed significant differences when comparing CCNG1 nuclear staining percentages between analogous healthy and cancerous tissues (p = 0.002, df = 11). The nuclear staining percentages of CCNG1 and Ki-67 share a statistically significant, positive correlation (r = .936977, p Conclusion: Taken together, these data indicate that (1) CCNG1 expression, is frequently enhanced in cancerous tumors compared to their normal analogous counterparts, and (2) the level of CCNG1 expression may change over time, necessitating real time analysis in order to determine the optimal timing for CCNG1 inhibitor therapy. A Phase 2 basket study of DeltaRex-G cell cycle checkpoint inhibitor therapy is planned to correlate treatment outcome parameters with CCNG1 expression in patients’ tumors and circulating tumor cells. Citation Format: Erlinda M. Gordon, Christopher Szeto, Joshua R. Ravicz, Sandeep Reddy, Michael Morse, Sant Chawla, Frederick Hall. Enhanced expression of human Cyclin G1 (CCNG1) gene in metastatic cancer, a novel biomarker in development for CCNG1 inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2556.
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A Phase I-II Study Using Rexin-G Tumor-Targeted Retrovector Encoding a Dominant-Negative Cyclin G1 Inhibitor for Advanced Pancreatic Cancer
Elsevier, 2019Co-Authors: Sant P Chawla, Frederick L Hall, Howard Bruckner, Michael A. Morse, Nupur Assudani, Erlinda M GordonAbstract:Rexin-G is a replication-incompetent retroviral vector displaying a cryptic SIG-binding peptide for targeting abnormal Signature (SIG) proteins in tumors and encoding a dominant-negative human Cyclin G1 construct. Herein we report on the safety and antitumor activity of escalating doses of Rexin-G in gemcitabine-refractory pancreatic adenocarcinoma, with one 10-year survivor. For the safety analysis (n = 20), treatment-related grade 1 adverse events included fatigue (n = 6), chills (n = 2), and headache (n = 1), with no organ damage and no DLT. No patient tested positive for vector-neutralizing antibodies, antibodies to gp70, replication-competent retrovirus (RCR), or vector integration into genomic DNA of peripheral blood lymphocytes (PBLs). For the efficacy analysis (n = 15), one patient achieved a complete response (CR), two patients had a partial response (PR), and 12 had stable disease (SD). Median progression-free survival (PFS) was 2.7, 4.0, and 5.6 months at doses 0–I, II, and III, respectively. Median overall survival (OS) and 1-year OS rate at dose 0–I were 4.3 months and 0%, and at dose II–III they were 9.2 months and 33.3%. To date, one patient is still alive with no evidence of cancer 10 years after the start of Rexin-G treatment. Taken together, these data suggest that Rexin-G, the first targeted gene delivery system, is uniquely safe and exhibits significant antitumor activity, for which the FDA granted fast-track designation. Keywords: gene therapy, cell cycle control, 10-year cancer-free survivor, pancreas adenocarcinoma, Cyclin G1 inhibitor, retrovector, tumor targeting, targeted gene delivery, CCNG
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A Phase I-II Study Using Rexin-G Tumor-Targeted Retrovector Encoding a Dominant-Negative Cyclin G1 Inhibitor for Advanced Pancreatic Cancer.
Molecular therapy oncolytics, 2018Co-Authors: Sant P Chawla, Frederick L Hall, Michael A. Morse, Nupur Assudani, Howard W. Bruckner, Erlinda M GordonAbstract:Rexin-G is a replication-incompetent retroviral vector displaying a cryptic SIG-binding peptide for targeting abnormal Signature (SIG) proteins in tumors and encoding a dominant-negative human Cyclin G1 construct. Herein we report on the safety and antitumor activity of escalating doses of Rexin-G in gemcitabine-refractory pancreatic adenocarcinoma, with one 10-year survivor. For the safety analysis (n = 20), treatment-related grade 1 adverse events included fatigue (n = 6), chills (n = 2), and headache (n = 1), with no organ damage and no DLT. No patient tested positive for vector-neutralizing antibodies, antibodies to gp70, replication-competent retrovirus (RCR), or vector integration into genomic DNA of peripheral blood lymphocytes (PBLs). For the efficacy analysis (n = 15), one patient achieved a complete response (CR), two patients had a partial response (PR), and 12 had stable disease (SD). Median progression-free survival (PFS) was 2.7, 4.0, and 5.6 months at doses 0–I, II, and III, respectively. Median overall survival (OS) and 1-year OS rate at dose 0–I were 4.3 months and 0%, and at dose II–III they were 9.2 months and 33.3%. To date, one patient is still alive with no evidence of cancer 10 years after the start of Rexin-G treatment. Taken together, these data suggest that Rexin-G, the first targeted gene delivery system, is uniquely safe and exhibits significant antitumor activity, for which the FDA granted fast-track designation.
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cell cycle checkpoint control the Cyclin G1 mdm2 p53 axis emerges as a strategic target for broad spectrum cancer gene therapy a review of molecular mechanisms for oncologists
Molecular and Clinical Oncology, 2018Co-Authors: Erlinda M Gordon, Joshua Ravicz, Sant P Chawla, Frederick L HallAbstract:Basic research in genetics, biochemistry and cell biology has identified the executive enzymes and protein kinase activities that regulate the cell division cycle of all eukaryotic organisms, thereby elucidating the importance of site-specific protein phosphorylation events that govern cell cycle progression. Research in cancer genomics and virology has provided meaningful links to mammalian checkpoint control elements with the characterization of growth-promoting proto-oncogenes encoding c-Myc, Mdm2, Cyclins A, D1 and G1, and opposing tumor suppressor proteins, such as p53, pRb, p16INK4A and p21WAF1, which are commonly dysregulated in cancer. While progress has been made in identifying numerous enzymes and molecular interactions associated with cell cycle checkpoint control, the marked complexity, particularly the functional redundancy, of these cell cycle control enzymes in mammalian systems, presents a major challenge in discerning an optimal locus for therapeutic intervention in the clinical management of cancer. Recent advances in genetic engineering, functional genomics and clinical oncology converged in identifying Cyclin G1 (CCNG1 gene) as a pivotal component of a commanding Cyclin G1/Mdm2/p53 axis and a strategic locus for re-establishing cell cycle control by means of therapeutic gene transfer. The purpose of the present study is to provide a focused review of cycle checkpoint control as a practicum for clinical oncologists with an interest in applied molecular medicine. The aim is to present a unifying model that: i) clarifies the function of Cyclin G1 in establishing proliferative competence, overriding p53 checkpoints and advancing cell cycle progression; ii) is supported by studies of inhibitory microRNAs linking CCNG1 expression to the mechanisms of carcinogenesis and viral subversion; and iii) provides a mechanistic basis for understanding the broad-spectrum anticancer activity and single-agent efficacy observed with dominant-negative Cyclin G1, whose cytocidal mechanism of action triggers programmed cell death. Clinically, the utility of companion diagnostics for Cyclin G1 pathways is anticipated in the staging, prognosis and treatment of cancers, including the potential for rational combinatorial therapies.
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Cell cycle checkpoint control: The Cyclin G1/Mdm2/p53 axis emerges as a strategic target for broad‑spectrum cancer gene therapy - A review of molecular mechanisms for oncologists
Molecular and clinical oncology, 2018Co-Authors: Erlinda M Gordon, Joshua Ravicz, Sant P Chawla, Seiya Liu, Frederick L HallAbstract:Basic research in genetics, biochemistry and cell biology has identified the executive enzymes and protein kinase activities that regulate the cell division cycle of all eukaryotic organisms, thereby elucidating the importance of site-specific protein phosphorylation events that govern cell cycle progression. Research in cancer genomics and virology has provided meaningful links to mammalian checkpoint control elements with the characterization of growth-promoting proto-oncogenes encoding c-Myc, Mdm2, Cyclins A, D1 and G1, and opposing tumor suppressor proteins, such as p53, pRb, p16INK4A and p21WAF1, which are commonly dysregulated in cancer. While progress has been made in identifying numerous enzymes and molecular interactions associated with cell cycle checkpoint control, the marked complexity, particularly the functional redundancy, of these cell cycle control enzymes in mammalian systems, presents a major challenge in discerning an optimal locus for therapeutic intervention in the clinical management of cancer. Recent advances in genetic engineering, functional genomics and clinical oncology converged in identifying Cyclin G1 (CCNG1 gene) as a pivotal component of a commanding Cyclin G1/Mdm2/p53 axis and a strategic locus for re-establishing cell cycle control by means of therapeutic gene transfer. The purpose of the present study is to provide a focused review of cycle checkpoint control as a practicum for clinical oncologists with an interest in applied molecular medicine. The aim is to present a unifying model that: i) clarifies the function of Cyclin G1 in establishing proliferative competence, overriding p53 checkpoints and advancing cell cycle progression; ii) is supported by studies of inhibitory microRNAs linking CCNG1 expression to the mechanisms of carcinogenesis and viral subversion; and iii) provides a mechanistic basis for understanding the broad-spectrum anticancer activity and single-agent efficacy observed with dominant-negative Cyclin G1, whose cytocidal mechanism of action triggers programmed cell death. Clinically, the utility of companion diagnostics for Cyclin G1 pathways is anticipated in the staging, prognosis and treatment of cancers, including the potential for rational combinatorial therapies.
Erlinda M Gordon - One of the best experts on this subject based on the ideXlab platform.
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Abstract 2556: Enhanced expression of human Cyclin G1 (CCNG1) gene in metastatic cancer, a novel biomarker in development for CCNG1 inhibitor therapy
Molecular and Cellular Biology Genetics, 2019Co-Authors: Erlinda M Gordon, Joshua Ravicz, Sant P Chawla, Michael A. Morse, Christopher Szeto, Sandeep K. Reddy, Frederick L HallAbstract:Background: Metastatic cancer is associated with, hitherto, an invariably fatal outcome. DeltaRex-G, a CCNG1 inhibitor, has induced long term (9-12 year-) survivorship in patients with metastatic melanoma, sarcoma, lymphoma and cancer of pancreas and breast. Purpose: To evaluate CCNG1 expression in tumors as a novel biomarker for identification of patients who are likely to benefit from CCNG1 inhibitor therapy. Methods: RNA sequence analysis was used to compare CCNG1 expression in tumor (TCGA, N=9161) versus normal tissues (TGCA, N=678 and GTEx, N=7187) from 20 organ sites, and in primary vs metastatic melanoma (N=106 & 367 respectively). Using IHC staining, the significance of differences between the number of CCNG1+ and Ki-67+ cells in normal tissues vs tumors were evaluated using paired Student’s t test. Pearson’s coefficient of correlation was used to evaluate the relationship between the number of Ki-67+ vs CCNG1+ cells. Results: CCNG1 gene expression, by RNA sequence analysis, was significantly enhanced in melanoma, sarcoma, leukemia, and cancers of the lung, thyroid, brain, liver, prostate, testicle, head and neck, bladder, kidney, adrenal, cervix, and pancreas, compared to normal tissues (p = 0.006- 1.8E-58), and even greater, in metastatic vs primary melanoma. In a subset of melanoma tumors, there was overall positive correlation with progression/metastasis in both Ki67 and CCNG1 expression levels. Consistent with these findings, IHC showed significant differences when comparing CCNG1 nuclear staining percentages between analogous healthy and cancerous tissues (p = 0.002, df = 11). The nuclear staining percentages of CCNG1 and Ki-67 share a statistically significant, positive correlation (r = .936977, p Conclusion: Taken together, these data indicate that (1) CCNG1 expression, is frequently enhanced in cancerous tumors compared to their normal analogous counterparts, and (2) the level of CCNG1 expression may change over time, necessitating real time analysis in order to determine the optimal timing for CCNG1 inhibitor therapy. A Phase 2 basket study of DeltaRex-G cell cycle checkpoint inhibitor therapy is planned to correlate treatment outcome parameters with CCNG1 expression in patients’ tumors and circulating tumor cells. Citation Format: Erlinda M. Gordon, Christopher Szeto, Joshua R. Ravicz, Sandeep Reddy, Michael Morse, Sant Chawla, Frederick Hall. Enhanced expression of human Cyclin G1 (CCNG1) gene in metastatic cancer, a novel biomarker in development for CCNG1 inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2556.
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A Phase I-II Study Using Rexin-G Tumor-Targeted Retrovector Encoding a Dominant-Negative Cyclin G1 Inhibitor for Advanced Pancreatic Cancer
Elsevier, 2019Co-Authors: Sant P Chawla, Frederick L Hall, Howard Bruckner, Michael A. Morse, Nupur Assudani, Erlinda M GordonAbstract:Rexin-G is a replication-incompetent retroviral vector displaying a cryptic SIG-binding peptide for targeting abnormal Signature (SIG) proteins in tumors and encoding a dominant-negative human Cyclin G1 construct. Herein we report on the safety and antitumor activity of escalating doses of Rexin-G in gemcitabine-refractory pancreatic adenocarcinoma, with one 10-year survivor. For the safety analysis (n = 20), treatment-related grade 1 adverse events included fatigue (n = 6), chills (n = 2), and headache (n = 1), with no organ damage and no DLT. No patient tested positive for vector-neutralizing antibodies, antibodies to gp70, replication-competent retrovirus (RCR), or vector integration into genomic DNA of peripheral blood lymphocytes (PBLs). For the efficacy analysis (n = 15), one patient achieved a complete response (CR), two patients had a partial response (PR), and 12 had stable disease (SD). Median progression-free survival (PFS) was 2.7, 4.0, and 5.6 months at doses 0–I, II, and III, respectively. Median overall survival (OS) and 1-year OS rate at dose 0–I were 4.3 months and 0%, and at dose II–III they were 9.2 months and 33.3%. To date, one patient is still alive with no evidence of cancer 10 years after the start of Rexin-G treatment. Taken together, these data suggest that Rexin-G, the first targeted gene delivery system, is uniquely safe and exhibits significant antitumor activity, for which the FDA granted fast-track designation. Keywords: gene therapy, cell cycle control, 10-year cancer-free survivor, pancreas adenocarcinoma, Cyclin G1 inhibitor, retrovector, tumor targeting, targeted gene delivery, CCNG
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A Phase I-II Study Using Rexin-G Tumor-Targeted Retrovector Encoding a Dominant-Negative Cyclin G1 Inhibitor for Advanced Pancreatic Cancer.
Molecular therapy oncolytics, 2018Co-Authors: Sant P Chawla, Frederick L Hall, Michael A. Morse, Nupur Assudani, Howard W. Bruckner, Erlinda M GordonAbstract:Rexin-G is a replication-incompetent retroviral vector displaying a cryptic SIG-binding peptide for targeting abnormal Signature (SIG) proteins in tumors and encoding a dominant-negative human Cyclin G1 construct. Herein we report on the safety and antitumor activity of escalating doses of Rexin-G in gemcitabine-refractory pancreatic adenocarcinoma, with one 10-year survivor. For the safety analysis (n = 20), treatment-related grade 1 adverse events included fatigue (n = 6), chills (n = 2), and headache (n = 1), with no organ damage and no DLT. No patient tested positive for vector-neutralizing antibodies, antibodies to gp70, replication-competent retrovirus (RCR), or vector integration into genomic DNA of peripheral blood lymphocytes (PBLs). For the efficacy analysis (n = 15), one patient achieved a complete response (CR), two patients had a partial response (PR), and 12 had stable disease (SD). Median progression-free survival (PFS) was 2.7, 4.0, and 5.6 months at doses 0–I, II, and III, respectively. Median overall survival (OS) and 1-year OS rate at dose 0–I were 4.3 months and 0%, and at dose II–III they were 9.2 months and 33.3%. To date, one patient is still alive with no evidence of cancer 10 years after the start of Rexin-G treatment. Taken together, these data suggest that Rexin-G, the first targeted gene delivery system, is uniquely safe and exhibits significant antitumor activity, for which the FDA granted fast-track designation.
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cell cycle checkpoint control the Cyclin G1 mdm2 p53 axis emerges as a strategic target for broad spectrum cancer gene therapy a review of molecular mechanisms for oncologists
Molecular and Clinical Oncology, 2018Co-Authors: Erlinda M Gordon, Joshua Ravicz, Sant P Chawla, Frederick L HallAbstract:Basic research in genetics, biochemistry and cell biology has identified the executive enzymes and protein kinase activities that regulate the cell division cycle of all eukaryotic organisms, thereby elucidating the importance of site-specific protein phosphorylation events that govern cell cycle progression. Research in cancer genomics and virology has provided meaningful links to mammalian checkpoint control elements with the characterization of growth-promoting proto-oncogenes encoding c-Myc, Mdm2, Cyclins A, D1 and G1, and opposing tumor suppressor proteins, such as p53, pRb, p16INK4A and p21WAF1, which are commonly dysregulated in cancer. While progress has been made in identifying numerous enzymes and molecular interactions associated with cell cycle checkpoint control, the marked complexity, particularly the functional redundancy, of these cell cycle control enzymes in mammalian systems, presents a major challenge in discerning an optimal locus for therapeutic intervention in the clinical management of cancer. Recent advances in genetic engineering, functional genomics and clinical oncology converged in identifying Cyclin G1 (CCNG1 gene) as a pivotal component of a commanding Cyclin G1/Mdm2/p53 axis and a strategic locus for re-establishing cell cycle control by means of therapeutic gene transfer. The purpose of the present study is to provide a focused review of cycle checkpoint control as a practicum for clinical oncologists with an interest in applied molecular medicine. The aim is to present a unifying model that: i) clarifies the function of Cyclin G1 in establishing proliferative competence, overriding p53 checkpoints and advancing cell cycle progression; ii) is supported by studies of inhibitory microRNAs linking CCNG1 expression to the mechanisms of carcinogenesis and viral subversion; and iii) provides a mechanistic basis for understanding the broad-spectrum anticancer activity and single-agent efficacy observed with dominant-negative Cyclin G1, whose cytocidal mechanism of action triggers programmed cell death. Clinically, the utility of companion diagnostics for Cyclin G1 pathways is anticipated in the staging, prognosis and treatment of cancers, including the potential for rational combinatorial therapies.
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Cell cycle checkpoint control: The Cyclin G1/Mdm2/p53 axis emerges as a strategic target for broad‑spectrum cancer gene therapy - A review of molecular mechanisms for oncologists
Molecular and clinical oncology, 2018Co-Authors: Erlinda M Gordon, Joshua Ravicz, Sant P Chawla, Seiya Liu, Frederick L HallAbstract:Basic research in genetics, biochemistry and cell biology has identified the executive enzymes and protein kinase activities that regulate the cell division cycle of all eukaryotic organisms, thereby elucidating the importance of site-specific protein phosphorylation events that govern cell cycle progression. Research in cancer genomics and virology has provided meaningful links to mammalian checkpoint control elements with the characterization of growth-promoting proto-oncogenes encoding c-Myc, Mdm2, Cyclins A, D1 and G1, and opposing tumor suppressor proteins, such as p53, pRb, p16INK4A and p21WAF1, which are commonly dysregulated in cancer. While progress has been made in identifying numerous enzymes and molecular interactions associated with cell cycle checkpoint control, the marked complexity, particularly the functional redundancy, of these cell cycle control enzymes in mammalian systems, presents a major challenge in discerning an optimal locus for therapeutic intervention in the clinical management of cancer. Recent advances in genetic engineering, functional genomics and clinical oncology converged in identifying Cyclin G1 (CCNG1 gene) as a pivotal component of a commanding Cyclin G1/Mdm2/p53 axis and a strategic locus for re-establishing cell cycle control by means of therapeutic gene transfer. The purpose of the present study is to provide a focused review of cycle checkpoint control as a practicum for clinical oncologists with an interest in applied molecular medicine. The aim is to present a unifying model that: i) clarifies the function of Cyclin G1 in establishing proliferative competence, overriding p53 checkpoints and advancing cell cycle progression; ii) is supported by studies of inhibitory microRNAs linking CCNG1 expression to the mechanisms of carcinogenesis and viral subversion; and iii) provides a mechanistic basis for understanding the broad-spectrum anticancer activity and single-agent efficacy observed with dominant-negative Cyclin G1, whose cytocidal mechanism of action triggers programmed cell death. Clinically, the utility of companion diagnostics for Cyclin G1 pathways is anticipated in the staging, prognosis and treatment of cancers, including the potential for rational combinatorial therapies.
Peng Xuan Liu - One of the best experts on this subject based on the ideXlab platform.
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Long term inhibition of neointima formation in balloon-injured rat arteries by intraluminal instillation of a matrix-targeted retroviral vector bearing a cytocidal mutant Cyclin G1 construct
International journal of molecular medicine, 2001Co-Authors: M. F. Prescott, Erlinda M Gordon, Peng Xuan Liu, Z. H. Chen, G. Liau, Frederick L HallAbstract:Restenosis from neointimal proliferation is a frequent complication of intracoronary stenting and catheter-based revascularization procedures. Currently, there is no known therapeutic strategy that has been sufficiently effective to warrant its widespread use. In the present study, the anti-proliferative properties of a matrix (collagen)-targeted retroviral vector bearing a mutant Cyclin G1 (DNT 41-249) construct was evaluated in vitro and in vivo. In controlled one-month efficacy studies, the intraluminal instillation of the mutant Cyclin G1 vector significantly inhibited neointima lesion formation in balloon-injured rat arteries without neointimal growth, associated necrosis or intense inflammatory reaction. Taken together, these data extend the potential utility of the matrix-targeted mutant Cyclin G1 retroviral vector for management of vascular restenosis.
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inhibition of metastatic tumor growth in nude mice by portal vein infusions of matrix targeted retroviral vectors bearing a cytocidal Cyclin G1 construct
Cancer Research, 2000Co-Authors: Erlinda M Gordon, Peng Xuan Liu, Zhen Hai Chen, Ling Liu, Michelle Whitley, Conway Gee, Susan Groshen, David R Hinton, Robert W Beart, Frederick L HallAbstract:Tumor invasion and associated angiogenesis evoke a remodeling of extracellular matrix components. Retroviral vectors bearing auxiliary matrix-targeting motifs (ie., collagen-binding polypeptides) accumulate at sites of newly exposed collagen, thus promoting tumor site-specific gene delivery. In this study, we assessed the antitumor effects of serial portal vein infusions of matrix-targeted vectors bearing a mutant Cyclin G1 (dnG1) construct in a nude mouse model of liver metastasis. The size of tumor foci was dramatically reduced in dnG1 vector-treated mice compared with that in control vector- or PBS-treated animals (P = 0.0002). These findings represent a definitive advance in the development of targeted injectable vectors for metastatic cancer.
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Downregulation of Cyclin G1 expression by retrovirus-mediated antisense gene transfer inhibits vascular smooth muscle cell proliferation and neointima formation.
Circulation, 1997Co-Authors: Nian Ling Zhu, Erlinda M Gordon, Peng Xuan Liu, Wayne F. Anderson, Vaughn A. Starnes, Frederick L HallAbstract:Background The contemporary treatment of coronary athero-occlusive disease by percutaneous transluminal coronary angioplasty is hampered by maladaptive wound healing, resulting in significant failure rates. Morbid sequelae include smooth muscle cell (SMC) hyperplasia and restenosis due to vascular neointima formation. Methods and Results In this study, we examined the inhibitory effects of a concentrated retroviral vector bearing an antisense Cyclin G1 gene on aortic SMC proliferation in vitro and on neointima formation in vivo in a rat carotid injury model of restenosis. Retroviral vectors bearing an antisense Cyclin G1 construct inhibited the proliferation of transduced aortic SMCs in 2- to 6-day cultures, concomitant with downregulation of Cyclin G1 protein expression and decreased [3H]thymidine incorporation into DNA. Morphological examination showed evidence of cytolysis, giant syncytia formation, and apoptotic changes evidenced by overt cell shrinkage, nuclear fragmentation, and specific immunostain...
Wen Wen - One of the best experts on this subject based on the ideXlab platform.
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Cyclin G1 expands liver tumor initiating cells by sox2 induction via akt mtor signaling
Molecular Cancer Therapeutics, 2013Co-Authors: Wen Wen, Tao Han, Cheng Chen, Lei Huang, Wen Sun, Xue Wang, Liang Tang, Shuzhen Chen, Daimin Xiang, Dan CaoAbstract:Recurrence and chemoresistance of liver cancer has been attributed to the existence of liver tumor-initiating cells (T-ICs). It is important to decipher the molecular mechanism for acquisition of drug resistance and to design combinatorial therapeutic strategies. Cyclin G1 has been shown to play a pivotal role in initiation and metastasis of hepatocellular carcinoma. In this study, we found that enhanced Cyclin G1 expression was associated with drug resistance of hepatoma cells and higher recurrence rate in hepatocellular carcinoma patients. Expression of Cyclin G1 was elevated in liver T-ICs and closely correlated with the expression of liver T-IC markers. Forced Cyclin G1 expression remarkably enhanced self-renewal and tumorigenicity of hepatoma cells. Cyclin G1 overexpression dramatically upregulated the expression of Sox2 both in vitro and in vivo, which was impaired by chemical inhibitors of Akt/mTOR signaling. Furthermore, blockade of Akt/mTOR signaling or interference of Sox2 expression suppressed Cyclin G1-enhanced self-renewal, chemoresistance, and tumorigenicity of hepatoma cells, indicating that Cyclin G1 expands liver T-ICs through Sox2 induction via Akt/mTOR signaling pathway. These results suggest that Cyclin G1-induced liver T-IC expansion contributes to the recurrence and chemoresistance of hepatoma, and Cyclin G1 may be a promising biomarker for individualized therapy of hepatocellular carcinoma patients.
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Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction via Akt/mTOR Signaling
Molecular cancer therapeutics, 2013Co-Authors: Wen Wen, Tao Han, Cheng Chen, Lei Huang, Wen Sun, Xue Wang, Chen Shuzhen, Xiang Daimin, Liang Tang, Dan CaoAbstract:Recurrence and chemoresistance of liver cancer has been attributed to the existence of liver tumor-initiating cells (T-ICs). It is important to decipher the molecular mechanism for acquisition of drug resistance and to design combinatorial therapeutic strategies. Cyclin G1 has been shown to play a pivotal role in initiation and metastasis of hepatocellular carcinoma. In this study, we found that enhanced Cyclin G1 expression was associated with drug resistance of hepatoma cells and higher recurrence rate in hepatocellular carcinoma patients. Expression of Cyclin G1 was elevated in liver T-ICs and closely correlated with the expression of liver T-IC markers. Forced Cyclin G1 expression remarkably enhanced self-renewal and tumorigenicity of hepatoma cells. Cyclin G1 overexpression dramatically upregulated the expression of Sox2 both in vitro and in vivo, which was impaired by chemical inhibitors of Akt/mTOR signaling. Furthermore, blockade of Akt/mTOR signaling or interference of Sox2 expression suppressed Cyclin G1-enhanced self-renewal, chemoresistance, and tumorigenicity of hepatoma cells, indicating that Cyclin G1 expands liver T-ICs through Sox2 induction via Akt/mTOR signaling pathway. These results suggest that Cyclin G1-induced liver T-IC expansion contributes to the recurrence and chemoresistance of hepatoma, and Cyclin G1 may be a promising biomarker for individualized therapy of hepatocellular carcinoma patients.
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via Akt/mTOR Signaling Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction
2013Co-Authors: Wen Wen, Tao Han, Cheng ChenAbstract:Abstract Recurrenceandchemoresistanceoflivercancerhasbeenattributedtotheexistenceoflivertumor-initiatingcells (T-ICs). It is important to decipher the molecular mechanism for acquisition of drug resistance and todesign combinatorial therapeutic strategies. Cyclin G1 has been shown to play a pivotal role in initiation andmetastasis of hepatocellular carcinoma. In this study, we found that enhanced Cyclin G1 expression wasassociated with drug resistance of hepatoma cells and higher recurrence rate in hepatocellular carcinomapatients.ExpressionofCyclinG1waselevatedinliverT-ICsandcloselycorrelatedwiththeexpressionofliverT-ICmarkers.ForcedCyclinG1expressionremarkablyenhancedself-renewalandtumorigenicityofhepatomacells.CyclinG1overexpressiondramaticallyupregulatedtheexpressionofSox2bothinvitroandinvivo,whichwasimpairedbychemicalinhibitorsofAkt/mTORsignaling.Furthermore,blockadeofAkt/mTORsignalingor interference of Sox2 expression suppressed Cyclin G1–enhanced self-renewal, chemoresistance, andtumorigenicity of hepatoma cells, indicating that Cyclin G1 expands liver T-ICs through Sox2 induction viaAkt/mTORsignalingpathway.TheseresultssuggestthatCyclinG1–inducedliverT-ICexpansioncontributesto the recurrence and chemoresistance of hepatoma, and Cyclin G1 may be a promising biomarker forindividualized therapy of hepatocellular carcinoma patients. Mol Cancer Ther; 12(9); 1796–804. 2013 AACR.
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Cyclin G1 mediated epithelial mesenchymal transition via phosphoinositide 3 kinase akt signaling facilitates liver cancer progression
Hepatology, 2012Co-Authors: Wen Wen, Tao Han, Cheng Chen, Lei Huang, Wen Sun, Jin Ding, Yao Chen, Bei-fang Ning, Dong Xie, Gensheng FengAbstract:Cyclin G1 deficiency is associated with reduced incidence of carcinogen-induced hepatocellular carcinoma (HCC), but its function in HCC progression remains obscure. We report a critical role of Cyclin G1 in HCC metastasis. Elevated expression of Cyclin G1 was detected in HCCs (60.6%), and its expression levels were even higher in portal vein tumor thrombus. Clinicopathological analysis revealed a close correlation of Cyclin G1 expression with distant metastasis and poor prognosis of HCC. Forced expression of Cyclin G1 promoted epithelial-mesenchymal transition (EMT) and metastasis of HCC cells in vitro and in vivo. Cyclin G1 overexpression enhanced Akt activation through interaction with p85 (regulatory subunit of phosphoinositide 3-kinase [PI3K]), which led to subsequent phosphorylation of glycogen synthase kinase-3β (GSK-3β) and stabilization of Snail, a critical EMT mediator. These results suggest that elevated Cyclin G1 facilitates HCC metastasis by promoting EMT via PI3K/Akt/GSK-3β/Snail-dependent pathway. Consistently, we have observed a significant correlation between Cyclin G1 expression and p-Akt levels in a cohort of HCC patients, and found that combination of these two parameters is a more powerful predictor of poor prognosis. Conclusions: Cyclin G1 plays a pivotal role in HCC metastasis and may serve as a novel prognostic biomarker and therapeutic target. (HEPATOLOGY 2012;55:1787–1798)
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Cyclin G1–mediated epithelial-mesenchymal transition via phosphoinositide 3-kinase/Akt signaling facilitates liver cancer progression†
Hepatology (Baltimore Md.), 2012Co-Authors: Wen Wen, Tao Han, Lei Huang, Wen Sun, Jin Ding, Yao Chen, Bei-fang Ning, Cheng ChenAbstract:Cyclin G1 deficiency is associated with reduced incidence of carcinogen-induced hepatocellular carcinoma (HCC), but its function in HCC progression remains obscure. We report a critical role of Cyclin G1 in HCC metastasis. Elevated expression of Cyclin G1 was detected in HCCs (60.6%), and its expression levels were even higher in portal vein tumor thrombus. Clinicopathological analysis revealed a close correlation of Cyclin G1 expression with distant metastasis and poor prognosis of HCC. Forced expression of Cyclin G1 promoted epithelial-mesenchymal transition (EMT) and metastasis of HCC cells in vitro and in vivo. Cyclin G1 overexpression enhanced Akt activation through interaction with p85 (regulatory subunit of phosphoinositide 3-kinase [PI3K]), which led to subsequent phosphorylation of glycogen synthase kinase-3β (GSK-3β) and stabilization of Snail, a critical EMT mediator. These results suggest that elevated Cyclin G1 facilitates HCC metastasis by promoting EMT via PI3K/Akt/GSK-3β/Snail-dependent pathway. Consistently, we have observed a significant correlation between Cyclin G1 expression and p-Akt levels in a cohort of HCC patients, and found that combination of these two parameters is a more powerful predictor of poor prognosis. Conclusions: Cyclin G1 plays a pivotal role in HCC metastasis and may serve as a novel prognostic biomarker and therapeutic target. (HEPATOLOGY 2012;55:1787–1798)
Cheng Chen - One of the best experts on this subject based on the ideXlab platform.
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Cyclin G1 expands liver tumor initiating cells by sox2 induction via akt mtor signaling
Molecular Cancer Therapeutics, 2013Co-Authors: Wen Wen, Tao Han, Cheng Chen, Lei Huang, Wen Sun, Xue Wang, Liang Tang, Shuzhen Chen, Daimin Xiang, Dan CaoAbstract:Recurrence and chemoresistance of liver cancer has been attributed to the existence of liver tumor-initiating cells (T-ICs). It is important to decipher the molecular mechanism for acquisition of drug resistance and to design combinatorial therapeutic strategies. Cyclin G1 has been shown to play a pivotal role in initiation and metastasis of hepatocellular carcinoma. In this study, we found that enhanced Cyclin G1 expression was associated with drug resistance of hepatoma cells and higher recurrence rate in hepatocellular carcinoma patients. Expression of Cyclin G1 was elevated in liver T-ICs and closely correlated with the expression of liver T-IC markers. Forced Cyclin G1 expression remarkably enhanced self-renewal and tumorigenicity of hepatoma cells. Cyclin G1 overexpression dramatically upregulated the expression of Sox2 both in vitro and in vivo, which was impaired by chemical inhibitors of Akt/mTOR signaling. Furthermore, blockade of Akt/mTOR signaling or interference of Sox2 expression suppressed Cyclin G1-enhanced self-renewal, chemoresistance, and tumorigenicity of hepatoma cells, indicating that Cyclin G1 expands liver T-ICs through Sox2 induction via Akt/mTOR signaling pathway. These results suggest that Cyclin G1-induced liver T-IC expansion contributes to the recurrence and chemoresistance of hepatoma, and Cyclin G1 may be a promising biomarker for individualized therapy of hepatocellular carcinoma patients.
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Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction via Akt/mTOR Signaling
Molecular cancer therapeutics, 2013Co-Authors: Wen Wen, Tao Han, Cheng Chen, Lei Huang, Wen Sun, Xue Wang, Chen Shuzhen, Xiang Daimin, Liang Tang, Dan CaoAbstract:Recurrence and chemoresistance of liver cancer has been attributed to the existence of liver tumor-initiating cells (T-ICs). It is important to decipher the molecular mechanism for acquisition of drug resistance and to design combinatorial therapeutic strategies. Cyclin G1 has been shown to play a pivotal role in initiation and metastasis of hepatocellular carcinoma. In this study, we found that enhanced Cyclin G1 expression was associated with drug resistance of hepatoma cells and higher recurrence rate in hepatocellular carcinoma patients. Expression of Cyclin G1 was elevated in liver T-ICs and closely correlated with the expression of liver T-IC markers. Forced Cyclin G1 expression remarkably enhanced self-renewal and tumorigenicity of hepatoma cells. Cyclin G1 overexpression dramatically upregulated the expression of Sox2 both in vitro and in vivo, which was impaired by chemical inhibitors of Akt/mTOR signaling. Furthermore, blockade of Akt/mTOR signaling or interference of Sox2 expression suppressed Cyclin G1-enhanced self-renewal, chemoresistance, and tumorigenicity of hepatoma cells, indicating that Cyclin G1 expands liver T-ICs through Sox2 induction via Akt/mTOR signaling pathway. These results suggest that Cyclin G1-induced liver T-IC expansion contributes to the recurrence and chemoresistance of hepatoma, and Cyclin G1 may be a promising biomarker for individualized therapy of hepatocellular carcinoma patients.
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via Akt/mTOR Signaling Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction
2013Co-Authors: Wen Wen, Tao Han, Cheng ChenAbstract:Abstract Recurrenceandchemoresistanceoflivercancerhasbeenattributedtotheexistenceoflivertumor-initiatingcells (T-ICs). It is important to decipher the molecular mechanism for acquisition of drug resistance and todesign combinatorial therapeutic strategies. Cyclin G1 has been shown to play a pivotal role in initiation andmetastasis of hepatocellular carcinoma. In this study, we found that enhanced Cyclin G1 expression wasassociated with drug resistance of hepatoma cells and higher recurrence rate in hepatocellular carcinomapatients.ExpressionofCyclinG1waselevatedinliverT-ICsandcloselycorrelatedwiththeexpressionofliverT-ICmarkers.ForcedCyclinG1expressionremarkablyenhancedself-renewalandtumorigenicityofhepatomacells.CyclinG1overexpressiondramaticallyupregulatedtheexpressionofSox2bothinvitroandinvivo,whichwasimpairedbychemicalinhibitorsofAkt/mTORsignaling.Furthermore,blockadeofAkt/mTORsignalingor interference of Sox2 expression suppressed Cyclin G1–enhanced self-renewal, chemoresistance, andtumorigenicity of hepatoma cells, indicating that Cyclin G1 expands liver T-ICs through Sox2 induction viaAkt/mTORsignalingpathway.TheseresultssuggestthatCyclinG1–inducedliverT-ICexpansioncontributesto the recurrence and chemoresistance of hepatoma, and Cyclin G1 may be a promising biomarker forindividualized therapy of hepatocellular carcinoma patients. Mol Cancer Ther; 12(9); 1796–804. 2013 AACR.
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Cyclin G1 mediated epithelial mesenchymal transition via phosphoinositide 3 kinase akt signaling facilitates liver cancer progression
Hepatology, 2012Co-Authors: Wen Wen, Tao Han, Cheng Chen, Lei Huang, Wen Sun, Jin Ding, Yao Chen, Bei-fang Ning, Dong Xie, Gensheng FengAbstract:Cyclin G1 deficiency is associated with reduced incidence of carcinogen-induced hepatocellular carcinoma (HCC), but its function in HCC progression remains obscure. We report a critical role of Cyclin G1 in HCC metastasis. Elevated expression of Cyclin G1 was detected in HCCs (60.6%), and its expression levels were even higher in portal vein tumor thrombus. Clinicopathological analysis revealed a close correlation of Cyclin G1 expression with distant metastasis and poor prognosis of HCC. Forced expression of Cyclin G1 promoted epithelial-mesenchymal transition (EMT) and metastasis of HCC cells in vitro and in vivo. Cyclin G1 overexpression enhanced Akt activation through interaction with p85 (regulatory subunit of phosphoinositide 3-kinase [PI3K]), which led to subsequent phosphorylation of glycogen synthase kinase-3β (GSK-3β) and stabilization of Snail, a critical EMT mediator. These results suggest that elevated Cyclin G1 facilitates HCC metastasis by promoting EMT via PI3K/Akt/GSK-3β/Snail-dependent pathway. Consistently, we have observed a significant correlation between Cyclin G1 expression and p-Akt levels in a cohort of HCC patients, and found that combination of these two parameters is a more powerful predictor of poor prognosis. Conclusions: Cyclin G1 plays a pivotal role in HCC metastasis and may serve as a novel prognostic biomarker and therapeutic target. (HEPATOLOGY 2012;55:1787–1798)
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Cyclin G1–mediated epithelial-mesenchymal transition via phosphoinositide 3-kinase/Akt signaling facilitates liver cancer progression†
Hepatology (Baltimore Md.), 2012Co-Authors: Wen Wen, Tao Han, Lei Huang, Wen Sun, Jin Ding, Yao Chen, Bei-fang Ning, Cheng ChenAbstract:Cyclin G1 deficiency is associated with reduced incidence of carcinogen-induced hepatocellular carcinoma (HCC), but its function in HCC progression remains obscure. We report a critical role of Cyclin G1 in HCC metastasis. Elevated expression of Cyclin G1 was detected in HCCs (60.6%), and its expression levels were even higher in portal vein tumor thrombus. Clinicopathological analysis revealed a close correlation of Cyclin G1 expression with distant metastasis and poor prognosis of HCC. Forced expression of Cyclin G1 promoted epithelial-mesenchymal transition (EMT) and metastasis of HCC cells in vitro and in vivo. Cyclin G1 overexpression enhanced Akt activation through interaction with p85 (regulatory subunit of phosphoinositide 3-kinase [PI3K]), which led to subsequent phosphorylation of glycogen synthase kinase-3β (GSK-3β) and stabilization of Snail, a critical EMT mediator. These results suggest that elevated Cyclin G1 facilitates HCC metastasis by promoting EMT via PI3K/Akt/GSK-3β/Snail-dependent pathway. Consistently, we have observed a significant correlation between Cyclin G1 expression and p-Akt levels in a cohort of HCC patients, and found that combination of these two parameters is a more powerful predictor of poor prognosis. Conclusions: Cyclin G1 plays a pivotal role in HCC metastasis and may serve as a novel prognostic biomarker and therapeutic target. (HEPATOLOGY 2012;55:1787–1798)
