The Experts below are selected from a list of 1950 Experts worldwide ranked by ideXlab platform
Youngeun Lee - One of the best experts on this subject based on the ideXlab platform.
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preclinical biosafety evaluation of genetically modified human adipose tissue derived mesenchymal stem cells for clinical applications to Brainstem Glioma
Stem Cells and Development, 2016Co-Authors: Seung Ah Choi, Ji Yeoun Lee, Pil Ae Kwak, Youngeun Lee, Kyeung Min Joo, Jun Won YunAbstract:Stem-cell based gene therapy is a promising novel therapeutic approach for inoperable invasive tumors, including Brainstem Glioma. Previously, we demonstrated the therapeutic potential of human adipose tissue-derived mesenchymal stem cells (hAT-MSC) genetically engineered to express a secreted form of tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) against Brainstem Glioma. However, safety concerns should be comprehensively investigated before clinical applications of hAT-MSC.sTRAIL. At first, we injected stereotactically low (1.2 × 10(5) cells/18 μL), medium (2.4 × 10(5)/18 μL), or high dose (3.6 × 10(5)/18 μL) of hAT-MSC.sTRAIL into the Brainstems of immunodeficient mice reflecting the plan of the future clinical trial. Local toxicity, systemic toxicity, secondary tumor formation, and biodistribution of hAT-MSC.sTRAIL were investigated. Next, presence of hAT-MSC.sTRAIL was confirmed in the brain and major organs at 4, 9, and 14 weeks in Brainstem Glioma-bearing mice. In the 15-week subchronic toxicity test, no serious adverse events in terms of body weight, food consumption, clinical symptom, urinalysis, hematology, clinical chemistry, organ weight, and histopathology were observed. In the 26-week tumorigenicity test, hAT-MSC.sTRAIL made no detectable tumors, whereas positive control U-87 MG cells made huge tumors in the Brainstem. No remaining hAT-MSC.sTRAIL was observed in any organs examined, including the Brainstem at 15 or 26 weeks. In Brainstem Glioma-bearing mice, injected hAT-MSC.sTRAIL was observed, but gradually decreased over time in the brain. The mRNA of human specific GAPDH and TRAIL was not detected in all major organs. These results indicate that the hAT-MSC.sTRAIL could be applicable to the future clinical trials in terms of biosafety.
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abstract 3544 clinical applicable human adipose tissue derived mesenchymal stem cells delivering therapeutic genes to Brainstem Glioma
Cancer Research, 2015Co-Authors: Seung Ah Choi, Kyu-chang Wang, Ji Hoon Phi, Youngeun Lee, Phil Ae Kwak, Youn Joo Moon, Sung Su Kim, Kyeung Min Joo, Seung-ki KimAbstract:Brainstem Glioma is one of incurable malignancies in children due to its unique inoperable location. Regarding the extensive migratory ability toward cancer and the possible autologous transplantation, human adipose-derived mesenchymal stem cells (hAT-MSC) are attractive vehicles to deliver therapeutic genes to Brainstem Glioma. In this study, we established clinically applicable hAT-MSCs expressing therapeutic genes in a GMP facility and investigated the therapeutic efficacy against Brainstem Glioma preclinically. For the feasible clinical application, 1) hAT-MSCs were primarily cultured from the human subcutaneous adipose tissue for making autologous transplantation possible, 2) hAT-MSCs were genetically engineered to express two therapeutic genes, carboxyl esterase (CE) and a secreted form of the TNF-related apoptosis-inducing ligand (sTRAIL) for synergistic effects, 3) human CE and sTRAIL sequences were utilized to avoid immunological side effects, and 4) sTRAIL expression vector was delivered by non-gDNA integrating gene transfer technology. hAT-MSCs expressing sTRAIL ± CE showed significant therapeutic effects against Brainstem Gliomas in vitro and in vivo. However, simultaneous sTRAIL and CE expression failed to show synergistic effects in vivo. The results indicate that non-viral transient sTRAIL gene transfer to autologous hAT-MSCs is a clinically applicable stem cell-based gene therapy for Brainstem Gliomas in terms of therapeutic effects and safety. Citation Format: Seung Ah Choi, Young Eun Lee, Phil Ae Kwak, Youn Joo Moon, Ji Hoon Phi, Kyu-Chang Wang, Sung Su Kim, Kyu-Chang Wang, Kyeung Min Joo, Seung-Ki Kim. Clinical applicable human adipose tissue-derived mesenchymal stem cells delivering therapeutic genes to Brainstem Glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3544. doi:10.1158/1538-7445.AM2015-3544
Seung Ah Choi - One of the best experts on this subject based on the ideXlab platform.
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Abstract 3195: Synergistic effects of combined treatment with hAT-MSC.sTRAIL and panobinostat in Brainstem Glioma
Clinical Research (Excluding Clinical Trials), 2016Co-Authors: Seung Ah Choi, Kyu-chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Chanhee Lee, Pil Ae Kwak, Sangjoon Chong, Seung-ki KimAbstract:Human adipose-derived mesenchymal stem cells expressing secreted form of the tumor necrosis factor-related apoptosis-inducing ligand (hAT-MSC.sTRAIL) have demonstrated therapeutic activity against various tumors. However, sTRAIL resistance remains a challenge in developing anticancer strategies. To solve this problem, many studies have tried to combine drugs to produce synergism or sensitize resistant cancer cells. Histone deacetylase inhibitors (HDACi) have been known to induce expression of TRAIL death receptors 4 and 5 (DR4/DR5). Herein, we evaluated the use of combined therapy of hAT-MSC.sTRAIL with HDAC inhibitor, panobinostat, in enhancing sensitivity to hAT-MSC.sTRAIL mediated apoptosis against the Brainstem Glioma. A sTRAIL was introduced into the characterized hAT-MSCs using electroporation. To confirm appropriate treatment concentration of panobinostat to the glioblastoma cells, dose titration was tested using cell viability assay. The therapeutic effect of single or combination treatment against glioblastoma was evaluated using primary cultured glioblastoma cells and cell lines. Orthotopic xenograft Brainstem Glioma mouse model was established using engineered firefly luciferase expressing tumor cells for bioluminescence in vivo imaging. Panobinostat induced anti-proliferative effects in dose and time-dependent manner (IC50 range, 0.05-0.2 μM) and effectively enhanced the expression of TRAIL DR4 and DR5, but not decoy receptors. Combined hAT-MSC.sTRAIL and panobinostat significantly decreased the tumor cell growth compared to each alone. Intriguingly, the combination treatment not only induced apoptosis but also autophagy. Using a preclinical Brainstem mouse model, we confirmed that the combination of hAT-MSC.sTRAIL and panobinostat was safe and induced regression of tumor volume. Furthermore, the combination therapy prolonged the survival of Brainstem Glioma-bearing mice. Our results suggested that combination therapy of panobinostat enhanced the anti-cancer effect of hAT-MSC.sTRAIL and represent potential therapeutic approach to the Brainstem Glioma. Citation Format: Seung Ah Choi, Chanhee Lee, Pil Ae Kwak, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Sangjoon Chong, Seung-Ki Kim. Synergistic effects of combined treatment with hAT-MSC.sTRAIL and panobinostat in Brainstem Glioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3195.
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preclinical biosafety evaluation of genetically modified human adipose tissue derived mesenchymal stem cells for clinical applications to Brainstem Glioma
Stem Cells and Development, 2016Co-Authors: Seung Ah Choi, Ji Yeoun Lee, Pil Ae Kwak, Youngeun Lee, Kyeung Min Joo, Jun Won YunAbstract:Stem-cell based gene therapy is a promising novel therapeutic approach for inoperable invasive tumors, including Brainstem Glioma. Previously, we demonstrated the therapeutic potential of human adipose tissue-derived mesenchymal stem cells (hAT-MSC) genetically engineered to express a secreted form of tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) against Brainstem Glioma. However, safety concerns should be comprehensively investigated before clinical applications of hAT-MSC.sTRAIL. At first, we injected stereotactically low (1.2 × 10(5) cells/18 μL), medium (2.4 × 10(5)/18 μL), or high dose (3.6 × 10(5)/18 μL) of hAT-MSC.sTRAIL into the Brainstems of immunodeficient mice reflecting the plan of the future clinical trial. Local toxicity, systemic toxicity, secondary tumor formation, and biodistribution of hAT-MSC.sTRAIL were investigated. Next, presence of hAT-MSC.sTRAIL was confirmed in the brain and major organs at 4, 9, and 14 weeks in Brainstem Glioma-bearing mice. In the 15-week subchronic toxicity test, no serious adverse events in terms of body weight, food consumption, clinical symptom, urinalysis, hematology, clinical chemistry, organ weight, and histopathology were observed. In the 26-week tumorigenicity test, hAT-MSC.sTRAIL made no detectable tumors, whereas positive control U-87 MG cells made huge tumors in the Brainstem. No remaining hAT-MSC.sTRAIL was observed in any organs examined, including the Brainstem at 15 or 26 weeks. In Brainstem Glioma-bearing mice, injected hAT-MSC.sTRAIL was observed, but gradually decreased over time in the brain. The mRNA of human specific GAPDH and TRAIL was not detected in all major organs. These results indicate that the hAT-MSC.sTRAIL could be applicable to the future clinical trials in terms of biosafety.
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abstract 3544 clinical applicable human adipose tissue derived mesenchymal stem cells delivering therapeutic genes to Brainstem Glioma
Cancer Research, 2015Co-Authors: Seung Ah Choi, Kyu-chang Wang, Ji Hoon Phi, Youngeun Lee, Phil Ae Kwak, Youn Joo Moon, Sung Su Kim, Kyeung Min Joo, Seung-ki KimAbstract:Brainstem Glioma is one of incurable malignancies in children due to its unique inoperable location. Regarding the extensive migratory ability toward cancer and the possible autologous transplantation, human adipose-derived mesenchymal stem cells (hAT-MSC) are attractive vehicles to deliver therapeutic genes to Brainstem Glioma. In this study, we established clinically applicable hAT-MSCs expressing therapeutic genes in a GMP facility and investigated the therapeutic efficacy against Brainstem Glioma preclinically. For the feasible clinical application, 1) hAT-MSCs were primarily cultured from the human subcutaneous adipose tissue for making autologous transplantation possible, 2) hAT-MSCs were genetically engineered to express two therapeutic genes, carboxyl esterase (CE) and a secreted form of the TNF-related apoptosis-inducing ligand (sTRAIL) for synergistic effects, 3) human CE and sTRAIL sequences were utilized to avoid immunological side effects, and 4) sTRAIL expression vector was delivered by non-gDNA integrating gene transfer technology. hAT-MSCs expressing sTRAIL ± CE showed significant therapeutic effects against Brainstem Gliomas in vitro and in vivo. However, simultaneous sTRAIL and CE expression failed to show synergistic effects in vivo. The results indicate that non-viral transient sTRAIL gene transfer to autologous hAT-MSCs is a clinically applicable stem cell-based gene therapy for Brainstem Gliomas in terms of therapeutic effects and safety. Citation Format: Seung Ah Choi, Young Eun Lee, Phil Ae Kwak, Youn Joo Moon, Ji Hoon Phi, Kyu-Chang Wang, Sung Su Kim, Kyu-Chang Wang, Kyeung Min Joo, Seung-Ki Kim. Clinical applicable human adipose tissue-derived mesenchymal stem cells delivering therapeutic genes to Brainstem Glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3544. doi:10.1158/1538-7445.AM2015-3544
Kyeung Min Joo - One of the best experts on this subject based on the ideXlab platform.
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preclinical biosafety evaluation of genetically modified human adipose tissue derived mesenchymal stem cells for clinical applications to Brainstem Glioma
Stem Cells and Development, 2016Co-Authors: Seung Ah Choi, Ji Yeoun Lee, Pil Ae Kwak, Youngeun Lee, Kyeung Min Joo, Jun Won YunAbstract:Stem-cell based gene therapy is a promising novel therapeutic approach for inoperable invasive tumors, including Brainstem Glioma. Previously, we demonstrated the therapeutic potential of human adipose tissue-derived mesenchymal stem cells (hAT-MSC) genetically engineered to express a secreted form of tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) against Brainstem Glioma. However, safety concerns should be comprehensively investigated before clinical applications of hAT-MSC.sTRAIL. At first, we injected stereotactically low (1.2 × 10(5) cells/18 μL), medium (2.4 × 10(5)/18 μL), or high dose (3.6 × 10(5)/18 μL) of hAT-MSC.sTRAIL into the Brainstems of immunodeficient mice reflecting the plan of the future clinical trial. Local toxicity, systemic toxicity, secondary tumor formation, and biodistribution of hAT-MSC.sTRAIL were investigated. Next, presence of hAT-MSC.sTRAIL was confirmed in the brain and major organs at 4, 9, and 14 weeks in Brainstem Glioma-bearing mice. In the 15-week subchronic toxicity test, no serious adverse events in terms of body weight, food consumption, clinical symptom, urinalysis, hematology, clinical chemistry, organ weight, and histopathology were observed. In the 26-week tumorigenicity test, hAT-MSC.sTRAIL made no detectable tumors, whereas positive control U-87 MG cells made huge tumors in the Brainstem. No remaining hAT-MSC.sTRAIL was observed in any organs examined, including the Brainstem at 15 or 26 weeks. In Brainstem Glioma-bearing mice, injected hAT-MSC.sTRAIL was observed, but gradually decreased over time in the brain. The mRNA of human specific GAPDH and TRAIL was not detected in all major organs. These results indicate that the hAT-MSC.sTRAIL could be applicable to the future clinical trials in terms of biosafety.
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abstract 3544 clinical applicable human adipose tissue derived mesenchymal stem cells delivering therapeutic genes to Brainstem Glioma
Cancer Research, 2015Co-Authors: Seung Ah Choi, Kyu-chang Wang, Ji Hoon Phi, Youngeun Lee, Phil Ae Kwak, Youn Joo Moon, Sung Su Kim, Kyeung Min Joo, Seung-ki KimAbstract:Brainstem Glioma is one of incurable malignancies in children due to its unique inoperable location. Regarding the extensive migratory ability toward cancer and the possible autologous transplantation, human adipose-derived mesenchymal stem cells (hAT-MSC) are attractive vehicles to deliver therapeutic genes to Brainstem Glioma. In this study, we established clinically applicable hAT-MSCs expressing therapeutic genes in a GMP facility and investigated the therapeutic efficacy against Brainstem Glioma preclinically. For the feasible clinical application, 1) hAT-MSCs were primarily cultured from the human subcutaneous adipose tissue for making autologous transplantation possible, 2) hAT-MSCs were genetically engineered to express two therapeutic genes, carboxyl esterase (CE) and a secreted form of the TNF-related apoptosis-inducing ligand (sTRAIL) for synergistic effects, 3) human CE and sTRAIL sequences were utilized to avoid immunological side effects, and 4) sTRAIL expression vector was delivered by non-gDNA integrating gene transfer technology. hAT-MSCs expressing sTRAIL ± CE showed significant therapeutic effects against Brainstem Gliomas in vitro and in vivo. However, simultaneous sTRAIL and CE expression failed to show synergistic effects in vivo. The results indicate that non-viral transient sTRAIL gene transfer to autologous hAT-MSCs is a clinically applicable stem cell-based gene therapy for Brainstem Gliomas in terms of therapeutic effects and safety. Citation Format: Seung Ah Choi, Young Eun Lee, Phil Ae Kwak, Youn Joo Moon, Ji Hoon Phi, Kyu-Chang Wang, Sung Su Kim, Kyu-Chang Wang, Kyeung Min Joo, Seung-Ki Kim. Clinical applicable human adipose tissue-derived mesenchymal stem cells delivering therapeutic genes to Brainstem Glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3544. doi:10.1158/1538-7445.AM2015-3544
Oren J Becher - One of the best experts on this subject based on the ideXlab platform.
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ABCG2 and ABCB1 limit the efficacy of dasatinib in a PDGF-B driven Brainstem Glioma model
Molecular Cancer Therapeutics, 2016Co-Authors: Rajendar K Mittapalli, Donna Crabtree, Kyle G. Halvorson, Alexander H Chung, Guo Hu, Karen E Parrish, William F Elmquist, Oren J BecherAbstract:Dasatinib is a multikinase inhibitor in clinical trials for Glioma, and thus far has failed to demonstrate significant efficacy. We investigated whether the ABC efflux transporters ABCG2 and ABCB1 expressed in the blood–brain barrier (BBB), are limiting the efficacy of dasatinib in the treatment of Glioma using genetic and pharmacologic approaches. We utilized a genetic Brainstem Glioma mouse model driven by platelet-derived growth factor-B and p53 loss using abcg2/abcb1 wild-type (ABC WT) or abcg2/abcb1 knockout mice (ABC KO). First, we observed that Brainstem Glioma tumor latency is significantly prolonged in ABC KO versus ABC WT mice (median survival of 47 vs. 34 days). Dasatinib treatment nearly doubles the survival of Brainstem Glioma-bearing ABC KO mice (44 vs. 80 days). Elacridar, an ABCG2 and ABCB1 inhibitor, significantly increases the efficacy of dasatinib in Brainstem Glioma-bearing ABC WT mice (42 vs. 59 days). Pharmacokinetic analysis demonstrates that dasatinib delivery into the normal brain, but not into the tumor core, is significantly increased in ABC KO mice compared with ABC WT mice. Surprisingly, elacridar did not significantly increase dasatinib delivery into the normal brain or the tumor core of ABC WT mice. Next, we demonstrate that the tight junctions of the BBB of this model are compromised as assessed by tissue permeability to Texas Red dextran. Finally, elacridar increases the cytotoxicity of dasatinib independent of ABCG2 and ABCB1 expression in vitro . In conclusion, elacridar improves the efficacy of dasatinib in a Brainstem Glioma model without significantly increasing its delivery to the tumor core. Mol Cancer Ther; 15(5); 819–29. ©2016 AACR .
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ABCG2 and ABCB1 Limit the Efficacy of Dasatinib in a PDGF-B–Driven Brainstem Glioma Model
Molecular cancer therapeutics, 2016Co-Authors: Rajendar K Mittapalli, Kyle G. Halvorson, Alexander H Chung, Karen E Parrish, William F Elmquist, Donna M Crabtree, Oren J BecherAbstract:Dasatinib is a multikinase inhibitor in clinical trials for Glioma, and thus far has failed to demonstrate significant efficacy. We investigated whether the ABC efflux transporters ABCG2 and ABCB1 expressed in the blood-brain barrier (BBB), are limiting the efficacy of dasatinib in the treatment of Glioma using genetic and pharmacologic approaches. We utilized a genetic Brainstem Glioma mouse model driven by platelet-derived growth factor-B and p53 loss using abcg2/abcb1 wild-type (ABC WT) or abcg2/abcb1 knockout mice (ABC KO). First, we observed that Brainstem Glioma tumor latency is significantly prolonged in ABC KO versus ABC WT mice (median survival of 47 vs. 34 days). Dasatinib treatment nearly doubles the survival of Brainstem Glioma-bearing ABC KO mice (44 vs. 80 days). Elacridar, an ABCG2 and ABCB1 inhibitor, significantly increases the efficacy of dasatinib in Brainstem Glioma-bearing ABC WT mice (42 vs. 59 days). Pharmacokinetic analysis demonstrates that dasatinib delivery into the normal brain, but not into the tumor core, is significantly increased in ABC KO mice compared with ABC WT mice. Surprisingly, elacridar did not significantly increase dasatinib delivery into the normal brain or the tumor core of ABC WT mice. Next, we demonstrate that the tight junctions of the BBB of this model are compromised as assessed by tissue permeability to Texas Red dextran. Finally, elacridar increases the cytotoxicity of dasatinib independent of ABCG2 and ABCB1 expression in vitro In conclusion, elacridar improves the efficacy of dasatinib in a Brainstem Glioma model without significantly increasing its delivery to the tumor core. Mol Cancer Ther; 15(5); 819-29. ©2016 AACR.
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pax3 expression enhances pdgf b induced Brainstem Gliomagenesis and characterizes a subset of Brainstem Glioma
Acta neuropathologica communications, 2014Co-Authors: Katherine L Misuraca, Alexander H Chung, Kelly L. Barton, Alexander K Diaz, Simon J Conway, David L Corcoran, Suzanne J Baker, Oren J BecherAbstract:High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in Gliomagenesis such that BSG is considered a distinct disease from Glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the Brainstem Gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of Brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in Glioma. Ectopic expression of Pax3 in normal Brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of Brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven Gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human Glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced Brainstem Gliomagenesis.
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pd 0332991 a cdk4 6 inhibitor significantly prolongs survival in a genetically engineered mouse model of Brainstem Glioma
PLOS ONE, 2013Co-Authors: Kelly L. Barton, Katherine L Misuraca, Francisco Cordero, Elena Y Dobrikova, Hooney D Min, Matthias Gromeier, David G Kirsch, Oren J BecherAbstract:Diffuse intrinsic pontine Glioma (DIPG) is an incurable tumor that arises in the Brainstem of children. To date there is not a single approved drug to effectively treat these tumors and thus novel therapies are desperately needed. Recent studies suggest that a significant fraction of these tumors contain alterations in cell cycle regulatory genes including amplification of the D-type cyclins and CDK4/6, and less commonly, loss of Ink4a-ARF leading to aberrant cell proliferation. In this study, we evaluated the therapeutic approach of targeting the cyclin-CDK-Retinoblastoma (Rb) pathway in a genetically engineered PDGF-B-driven Brainstem Glioma (BSG) mouse model. We found that PD-0332991 (PD), a CDK4/6 inhibitor, induces cell-cycle arrest in our PDGF-B; Ink4a-ARF deficient model both in vitro and in vivo. By contrast, the PDGF-B; p53 deficient model was mostly resistant to treatment with PD. We noted that a 7-day treatment course with PD significantly prolonged survival by 12% in the PDGF-B; Ink4a-ARF deficient BSG model. Furthermore, a single dose of 10 Gy radiation therapy (RT) followed by 7 days of treatment with PD increased the survival by 19% in comparison to RT alone. These findings provide the rationale for evaluating PD in children with Ink4a-ARF deficient Gliomas.
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abstract 5004 ng2 upregulation and its defective asymmetric distribution in pediatric Brainstem Glioma and diffuse intrinsic pontine Glioma
Cancer Research, 2013Co-Authors: Sridevi Yadavilli, Oren J Becher, Madhuri Kambhampati, Tobey J Macdonald, Ravi V Bellamkonda, Roger J Paker, Javad NazarianAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Pediatric Brainstem Glioma (BSG) is one of the most difficult cancers to treat accounting for 10-20% of all pediatric central nervous system (CNS) tumors. BSGs may occur throughout the Brainstem and are categorized into two main groups: diffuse intrinsic pontine Gliomas (DIPGs) and focal Brainstem Gliomas. DIPGs represent about 80% of BSG and have a peak onset of six to nine years of age. DIPGs invade throughout the pons and may spread to other portions of Brainstem. To better understand the pathophysiology of the disease, a genetically engineered (PDGFα-expressing) BSG mouse and a xenograft model have been established. Results: We recently reported proteome profiling of DIPG CSF and formalin fixed specimens. To expand our molecular studies of the disease, we generated complete protein profiles of specimens obtained from BSG mouse tumor and aged-matched healthy controls. Neuroglia 2 (NG2), also known as chondroitine sulfate proteoglycan 4 (CSPG4) was selected for further analysis based on its exclusive expression in BSG specimens. Although NG2 has been previously implicated in adult Gliomas, its role in pediatric Gliomas has not been investigated and currently there are no publications on the role of NG2 in DIPGs. Recently, NG2 expression has been shown to play a significant role in neoplastic transformation of Glioma precursor cells. Gliomas are thought to originate from cells including astrocytes, stem cells, and Glioma progenitor cells. Glial progenitor cells are specifically important since several groups have reported detection of oligodendrocyte markers including NG2, PDGFRα, and Olig-2 in Gliomas. Our preliminary data shows high expression of NG2 in murine model of Brainstem Glioma as well as 80% of pediatric DIPG specimens tested. We show that shRNA-mediated knockdown of NG2 reduces cellular migration in vitro. NG2 expression is defective (symmetric) in dividing cells in vitro and in vivo. The defective NG2 expression is consistent with a recent observation in adult high grade Gliomas. Injection of NG2 expressing neurospheres (NS) into Brainstems of 2 day old mice (P2) results in highly aggressive Brainstem tumors resulting in death within 3-7 weeks post-injection. Therefore the NS injected mouse model of Brainstem Glioma provides a solid model for testing therapeutics and evaluating interventions. Furthermore, we show selective delivery of liposomal nanoparticles to Brainstem of our robust BSG mouse model. We also show that nanoparticle-mediated delivery of doxorubicin will induce apoptosis in tumor and not the adjacent normal region. Conclusion: We introduce a robust murine model of Brainstem Glioma that is developed using NG2 expressing cells. High expression of NG2 in a subset of DIPGs and its defective expression may provide novel approaches for treating DIPGs and BSGs. Citation Format: Sridevi Yadavilli, Madhuri Kambhampati, Oren J. Becher, Tobey MacDonald, Ravi Bellamkonda, Roger J. Paker, Javad Nazarian. NG2 upregulation and its defective asymmetric distribution in pediatric Brainstem Glioma and diffuse intrinsic pontine Glioma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5004. doi:10.1158/1538-7445.AM2013-5004
Ping Wang - One of the best experts on this subject based on the ideXlab platform.
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Clinical Efficacy of CyberKnife Radiosurgery for Adult Brainstem Glioma: 10 Years Experience at Tianjin CyberKnife Center and Review of the Literature.
Frontiers in oncology, 2019Co-Authors: Jiaqi Zhang, Qun Liu, Zhiyong Yuan, Lujun Zhao, Xiaoguang Wang, Ping WangAbstract:Abstract Background Brainstem Glioma is a rare brain tumor with poor prognosis and difficulty for surgical resection. We sought to retrospectively analyze and evaluate the clinical efficacy of CyberKnife for Brainstem Gliomas. Methods From 2006 to 2015, a total of 21 Brainstem Gliomas patients who received CyberKnife radiosurgery treatment enrolled in this study and 18 patients with follow up. CyberKnife image-guided radiosurgical system were applied consecutively with the median prescribed total dose of 26 Gy (14-33 Gy) at two to six fractions on days utilizing CyberKnife system, and the median biological equivalent doses of 59.8 Gy (33.6-76.56Gy). The clinic pathlogical features, survival were analyzed to explore the efficacy of CyberKnife radiosurgery in treatment of Brainstem Glioma. Results With median follow-up of 54.5 months, patients with Brainstem Gliomas had median overall survival of 19 months, 5 patients still alive. The primary endpoints of the 1- and 2-year overall survival rates were 87.5% and 52.4%, respectively. During the treatment course, six patients were observed to have pseudoprogression with mass effect on MRI. Four patients developed radiation complications. Grade 2 radiation-related toxicity were observed in three patients and one patient with grade 3. Conclusion The efficacy of Brainstem Gliomas – treated with CyberKnife is efficacious with mild toxicity.
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Clinical Efficacy of CyberKnife Radiosurgery for Adult Brainstem Glioma: 10 Years Experience at Tianjin CyberKnife Center and Review of the Literature
Frontiers Media S.A., 2019Co-Authors: Jiaqi Zhang, Qun Liu, Zhiyong Yuan, Lujun Zhao, Xiaoguang Wang, Ping WangAbstract:Background: Brainstem Glioma is a rare brain tumor with poor prognosis and difficulty for surgical resection. We sought to retrospectively analyze and evaluate the clinical efficacy of CyberKnife for Brainstem Gliomas.Methods: From 2006 to 2015, a total of 21 Brainstem Gliomas patients who received CyberKnife radiosurgery treatment enrolled in this study and 18 patients with follow up. CyberKnife image-guided radiosurgical system were applied consecutively with the median prescribed total dose of 26 Gy (14–33 Gy) at two to six fractions on days utilizing CyberKnife system, and the median biological equivalent doses of 59.8 Gy (33.6–76.56 Gy). The clinic pathlogical features, survival were analyzed to explore the efficacy of CyberKnife radiosurgery in treatment of Brainstem Glioma.Results: With median follow-up of 54.5 months, patients with Brainstem Gliomas had median overall survival of 19 months, five patients still alive. The primary endpoints of the 1- and 2-year overall survival rates were 87.5 and 52.4%, respectively. During the treatment course, six patients were observed to have pseudoprogression with mass effect on MRI. Four patients developed radiation complications. Grade 2 radiation-related toxicity were observed in three patients and one patient with grade 3.Conclusion: The efficacy of Brainstem Gliomas—treated with CyberKnife is efficacious with mild toxicity