The Experts below are selected from a list of 300 Experts worldwide ranked by ideXlab platform
Charles Keller - One of the best experts on this subject based on the ideXlab platform.
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protein kinase c iota as a therapeutic target in Alveolar Rhabdomyosarcoma
Oncogene, 2013Co-Authors: Ken Kikuchi, Laura D. Nelon, Sheila T. Hampton, Lee Ann Zarzabal, Brian P. Rubin, Anuradha Soundararajan, Capella Weems, Joel A Michalek, Alan P Fields, Charles KellerAbstract:Alveolar Rhabdomyosarcoma is an aggressive pediatric cancer exhibiting skeletal muscle differentiation. New therapeutic targets are required to improve the dismal prognosis for invasive or metastatic Alveolar Rhabdomyosarcoma. Protein kinase C iota (PKCι) has been shown to play an important role in tumorigenesis of many cancers but little is known about its role in Rhabdomyosarcoma. Our gene expression studies in human tumor samples revealed overexpression of PRKCI. We confirmed overexpression of PKCι at the mRNA and protein level using our conditional mouse model that authentically recapitulates the progression of Rhabdomyosarcoma in humans. Inhibition of Prkci by RNA interference resulted in a dramatic decrease in anchorage-independent colony formation. Interestingly, treatment of primary cell cultures using aurothiomalate (ATM), which is a gold-containing classical anti-rheumatic agent and a PKCι-specific inhibitor, resulted in decreased interaction between PKCι and Par6, decreased Rac1 activity and reduced cell viability at clinically relevant concentrations. Moreover, co-treatment with ATM and vincristine, a microtubule inhibitor currently used in Rhabdomyosarcoma treatment regimens, resulted in a combination index (C. I.) of 0.470–0.793 through cooperative accumulation of non-proliferative multinuclear cells in the G2/M phase, indicating that these two drugs synergize. For in vivo tumor growth inhibition studies, ATM demonstrated a trend towards enhanced vincristine sensitivity. Overall, these results suggest that PKCι is functionally important in Alveolar Rhabdomyosarcoma anchorage-independent growth and tumor cell proliferation and that combination therapy with ATM and microtubule inhibitors holds promise for the treatment of Alveolar Rhabdomyosarcoma.
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Preclinical Testing of Erlotinib in a Transgenic Alveolar Rhabdomyosarcoma Mouse Model
Sarcoma, 2011Co-Authors: Jinu Abraham, Laura D. Nelon, Courtney B. Kubicek, Aoife Kilcoyne, Sheila T. Hampton, Lee Ann Zarzabal, Francis J. Giles, Joel E. Michalek, Brian P. Rubin, Charles KellerAbstract:Rhabdomyosarcoma is an aggressive childhood malignancy, accounting for more than 50% of all soft-tissue sarcomas in children. Even with extensive therapy, the survival rate among Alveolar Rhabdomyosarcoma patients with advanced disease is only 20%. The receptor tyrosine kinase Epidermal Growth Factor Receptor (EGFR) has been found to be expressed and activated in human Rhabdomyosarcomas. In this study we have used a genetically engineered mouse model for Alveolar Rhabdomyosarcoma (ARMS) which faithfully recapitulates the human disease by activating the pathognomic Pax3:Fkhr fusion gene and inactivating p53 in the maturing myoblasts. We have demonstrated that tumors from our mouse model of Alveolar Rhabdomyosarcoma express EGFR at both the mRNA and protein levels. We then tested the EGFR inhibitor, Erlotinib, for its efficacy in this mouse model of Alveolar Rhabdomyosarcoma. Surprisingly, Erlotinib had no effect on tumor progression, yet mice treated with Erlotinib showed 10–20% loss of body weight. These results suggest that EGFR might not be an a priori monotherapy target in Alveolar Rhabdomyosarcoma.
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PDGFR-A is a therapeutic target in Alveolar Rhabdomyosarcoma
Cancer Research, 2008Co-Authors: Eri Taniguchi, Joel E. Michalek, Brian P. Rubin, Koichi Nishijo, Amanda T. Mccleish, Robin D. Legallo, Stephen J. Qualman, Hanna E. Abboud, Charles KellerAbstract:3750 Progression and metastasis of solid tumors is a principal cause of death for cancer patients. The childhood muscle cancer Alveolar Rhabdomyosarcoma is a classic example. A gap in understanding the disease-specific mechanisms of progression underlies the dismal outcome for patients with advanced Alveolar Rhabdomyosarcoma. Our initial studies of Rhabdomyosarcoma gene expression amongst patients enrolled in a national clinical trial suggest that the platelet-derived growth factor receptor A (PDGFR-A) may be a mediator of disease progression and metastasis. In our studies PDGFR-A has been found to be a transcriptional target of Pax3:Fkhr, the translocation-mediated fusion gene found in the majority of Alveolar Rhabdomyosarcomas. We hypothesize that PDGFR-A signaling pathways play a prominent role in progression and metastasis of Alveolar Rhabdomyosarcoma. To test this hypothesis, we have generated conditional mouse tumor models that authentically recapitulate the primary mutations and the metastatic progression of Alveolar Rhabdomyosarcomas in humans. We found that PDGFR-A and its downstream effecters, MAPK and Akt, were highly activated in both primary and metastasized tumor. We also confirmed that PDGFR-A, MAPK and Akt were activated in mouse and human Alveolar Rhabdomyosarcoma cell cultures, and that cell proliferation was inhibited by PDGFR-A specific siRNA. To determine the pathophysiological impact of PDGFR-A blockade for Rhabdomyosarcoma in vivo, we treated the receptor tyrosine kinase inhibitor, Imatinib, or PDGFR-A blocking antibody, which significantly inhibit tumor growth. These results establish proof-of-principal for PDGFR-A as a therapeutic target in childhood Alveolar Rhabdomyosarcomas.
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new genetic tactics to model Alveolar Rhabdomyosarcoma in the mouse
Cancer Research, 2005Co-Authors: Charles Keller, Mario R CapecchiAbstract:Using conditional knock-in and knock-out techniques, we designed a mouse model of the childhood muscle cancer Alveolar Rhabdomyosarcoma (ARMS) that is driven by the chromosomal translocation product, Pax3:Fkhr. Tumors that closely recapitulate the spectrum of molecular markers and histology seen in human ARMS are exclusively produced in this model. Unexpectedly, expression of Pax3:Fkhr in muscle satellite cells did not produce tumors, but it did in differentiating myofibers. Expression of Pax3:Fkhr in muscle is necessary but not sufficient to initiate tumorigenesis at high frequency. This model offers new insight into the roots of Alveolar Rhabdomyosarcoma and illustrates the utility of Cre-loxP technology for studying otherwise inaccessible cancers in the mouse.
B P Rubin - One of the best experts on this subject based on the ideXlab platform.
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PDGFR-A is a therapeutic target in Alveolar Rhabdomyosarcoma
Oncogene, 2008Co-Authors: E Taniguchi, Amanda T. Mccleish, Robin D. Legallo, Stephen J. Qualman, Hanna E. Abboud, Joel A Michalek, K Nishijo, M H Grayson, A J Infante, B P RubinAbstract:Alveolar Rhabdomyosarcoma is an aggressive skeletal muscle cancer of childhood. Our initial studies of Rhabdomyosarcoma gene expression for patients enrolled in a national clinical trial suggested that platelet-derived growth factor receptor A (PDGFR-A) may be a mediator of disease progression and metastasis. Using our conditional mouse tumor models that authentically recapitulate the primary mutations and metastatic progression of Alveolar Rhabdomyosarcomas in humans, we found by immunoblotting and immunokinase assays that PDGFR-A and its downstream effectors, mitogen-activated protein kinase and Akt, were highly activated in both primary and metastatic tumors. Inhibition of PDGFR-A by RNA interference, small molecule inhibitor or neutralizing antibody had a dramatic effect on tumor cell growth both in vitro and in vivo , although resistance evolved in one-third of tumors. These results establish proof-of-principal for PDGFR-A as a therapeutic target in Alveolar Rhabdomyosarcoma.
Andrew L Folpe - One of the best experts on this subject based on the ideXlab platform.
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Aberrant expression of epithelial and neuroendocrine markers in Alveolar Rhabdomyosarcoma: a potentially serious diagnostic pitfall
Modern Pathology, 2008Co-Authors: Armita Bahrami, Allen M Gown, Geoffrey S Baird, M John Hicks, Andrew L FolpeAbstract:Alveolar Rhabdomyosarcoma may be extremely difficult to distinguish from other primitive round cell neoplasms without ancillary immunohistochemistry and/or genetic study. Particularly in adults and in the head and neck locations, the differential diagnosis of Alveolar Rhabdomyosarcoma includes small cell carcinoma and neuroepithelial tumors, such as esthesioneuroblastoma. We have recently seen cases of genetically confirmed Alveolar Rhabdomyosarcoma, which were misdiagnosed owing to expression of cytokeratins and neuroendocrine markers. We studied a large group of well-characterized Alveolar Rhabdomyosarcomas for expression of such markers. Forty-four Alveolar Rhabdomyosarcomas (18 genetically confirmed) were retrieved from our archives and immunostained for wide-spectrum cytokeratin (OSCAR), low molecular weight cytokeratin (Cam5.2), synaptophysin, chromogranin A, and CD56 using commercially available antibodies. Cases were scored as ‘negative’, ‘rare’ (51%). The tumors occurred in 23 males and 21 females at a mean age of 18 years (range,
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aberrant expression of epithelial and neuroendocrine markers in Alveolar Rhabdomyosarcoma a potentially serious diagnostic pitfall
Modern Pathology, 2008Co-Authors: Armita Bahrami, Allen M Gown, Geoffrey S Baird, John M Hicks, Andrew L FolpeAbstract:Alveolar Rhabdomyosarcoma may be extremely difficult to distinguish from other primitive round cell neoplasms without ancillary immunohistochemistry and/or genetic study. Particularly in adults and in the head and neck locations, the differential diagnosis of Alveolar Rhabdomyosarcoma includes small cell carcinoma and neuroepithelial tumors, such as esthesioneuroblastoma. We have recently seen cases of genetically confirmed Alveolar Rhabdomyosarcoma, which were misdiagnosed owing to expression of cytokeratins and neuroendocrine markers. We studied a large group of well-characterized Alveolar Rhabdomyosarcomas for expression of such markers. Forty-four Alveolar Rhabdomyosarcomas (18 genetically confirmed) were retrieved from our archives and immunostained for wide-spectrum cytokeratin (OSCAR), low molecular weight cytokeratin (Cam5.2), synaptophysin, chromogranin A, and CD56 using commercially available antibodies. Cases were scored as ‘negative’, ‘rare’ ( 51%). The tumors occurred in 23 males and 21 females at a mean age of 18 years (range, <1–64 years), and involved many sites. Fifty percent of cases (22 of 44) expressed wide-spectrum cytokeratin, and scored almost equally as rare, 1+, and 2+, but rarely 3+. Cam5.2 was positive in 52% (14 of 27). Forty-three percent of cases (16 of 37) expressed at least one of the specific neuroendocrine markers, 32% (12 of 37) expressed synaptophysin, 22% (eight of 36) expressed chromogranin A, and 11% expressed both. Expression of synaptophysin and chromogranin A was typically confined to rare cells but could be more widespread. Thirty-two percent of cases (12 of 37) expressed the wide-spectrum cytokeratin and at least one of the neuroendocrine markers, and 8% (three of 36) expressed cytokeratin and both neuroendocrine markers. CD56 expression was nearly ubiquitous. Aberrant expression of epithelial and neuroendocrine markers is relatively common in Alveolar Rhabdomyosarcoma, occurring in 30–40% of cases. These findings have significant implications for the diagnosis of Alveolar Rhabdomyosarcoma, particularly in adults and in the head and neck locations. Although expression of cytokeratin and/or synaptophysin alone does not necessarily indicate epithelial or neuroendocrine differentiation, coexpression of cytokeratin and neuroendocrine markers, and in particular the presence of chromogranin expression, suggest true epithelial and/or neuroendocrine differentiation in a subset of Alveolar Rhabdomyosarcomas. CD56 is not a specific neuroendocrine marker, and should not be used in the absence of synaptophysin/chromogranin. These findings emphasize the need to employ a panel of markers, to include desmin, myogenin/MyoD1, and genetic study in the diagnosis of primitive round cell neoplasms in all age groups and in all locations.
Joel A Michalek - One of the best experts on this subject based on the ideXlab platform.
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protein kinase c iota as a therapeutic target in Alveolar Rhabdomyosarcoma
Oncogene, 2013Co-Authors: Ken Kikuchi, Laura D. Nelon, Sheila T. Hampton, Lee Ann Zarzabal, Brian P. Rubin, Anuradha Soundararajan, Capella Weems, Joel A Michalek, Alan P Fields, Charles KellerAbstract:Alveolar Rhabdomyosarcoma is an aggressive pediatric cancer exhibiting skeletal muscle differentiation. New therapeutic targets are required to improve the dismal prognosis for invasive or metastatic Alveolar Rhabdomyosarcoma. Protein kinase C iota (PKCι) has been shown to play an important role in tumorigenesis of many cancers but little is known about its role in Rhabdomyosarcoma. Our gene expression studies in human tumor samples revealed overexpression of PRKCI. We confirmed overexpression of PKCι at the mRNA and protein level using our conditional mouse model that authentically recapitulates the progression of Rhabdomyosarcoma in humans. Inhibition of Prkci by RNA interference resulted in a dramatic decrease in anchorage-independent colony formation. Interestingly, treatment of primary cell cultures using aurothiomalate (ATM), which is a gold-containing classical anti-rheumatic agent and a PKCι-specific inhibitor, resulted in decreased interaction between PKCι and Par6, decreased Rac1 activity and reduced cell viability at clinically relevant concentrations. Moreover, co-treatment with ATM and vincristine, a microtubule inhibitor currently used in Rhabdomyosarcoma treatment regimens, resulted in a combination index (C. I.) of 0.470–0.793 through cooperative accumulation of non-proliferative multinuclear cells in the G2/M phase, indicating that these two drugs synergize. For in vivo tumor growth inhibition studies, ATM demonstrated a trend towards enhanced vincristine sensitivity. Overall, these results suggest that PKCι is functionally important in Alveolar Rhabdomyosarcoma anchorage-independent growth and tumor cell proliferation and that combination therapy with ATM and microtubule inhibitors holds promise for the treatment of Alveolar Rhabdomyosarcoma.
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PDGFR-A is a therapeutic target in Alveolar Rhabdomyosarcoma
Oncogene, 2008Co-Authors: E Taniguchi, Amanda T. Mccleish, Robin D. Legallo, Stephen J. Qualman, Hanna E. Abboud, Joel A Michalek, K Nishijo, M H Grayson, A J Infante, B P RubinAbstract:Alveolar Rhabdomyosarcoma is an aggressive skeletal muscle cancer of childhood. Our initial studies of Rhabdomyosarcoma gene expression for patients enrolled in a national clinical trial suggested that platelet-derived growth factor receptor A (PDGFR-A) may be a mediator of disease progression and metastasis. Using our conditional mouse tumor models that authentically recapitulate the primary mutations and metastatic progression of Alveolar Rhabdomyosarcomas in humans, we found by immunoblotting and immunokinase assays that PDGFR-A and its downstream effectors, mitogen-activated protein kinase and Akt, were highly activated in both primary and metastatic tumors. Inhibition of PDGFR-A by RNA interference, small molecule inhibitor or neutralizing antibody had a dramatic effect on tumor cell growth both in vitro and in vivo , although resistance evolved in one-third of tumors. These results establish proof-of-principal for PDGFR-A as a therapeutic target in Alveolar Rhabdomyosarcoma.
Lee Ann Zarzabal - One of the best experts on this subject based on the ideXlab platform.
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rb1 loss modifies but does not initiate Alveolar Rhabdomyosarcoma
Skeletal Muscle, 2013Co-Authors: Ken Kikuchi, Jinu Abraham, Eri Taniguchi, Hungi Harry Chen, Matthew N Svalina, Elaine T Huang, Koichi Nishijo, Sean Davis, Christopher Louden, Lee Ann ZarzabalAbstract:Background Alveolar Rhabdomyosarcoma (aRMS) is a myogenic childhood sarcoma frequently associated with a translocation-mediated fusion gene, Pax3:Foxo1a.
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protein kinase c iota as a therapeutic target in Alveolar Rhabdomyosarcoma
Oncogene, 2013Co-Authors: Ken Kikuchi, Laura D. Nelon, Sheila T. Hampton, Lee Ann Zarzabal, Brian P. Rubin, Anuradha Soundararajan, Capella Weems, Joel A Michalek, Alan P Fields, Charles KellerAbstract:Alveolar Rhabdomyosarcoma is an aggressive pediatric cancer exhibiting skeletal muscle differentiation. New therapeutic targets are required to improve the dismal prognosis for invasive or metastatic Alveolar Rhabdomyosarcoma. Protein kinase C iota (PKCι) has been shown to play an important role in tumorigenesis of many cancers but little is known about its role in Rhabdomyosarcoma. Our gene expression studies in human tumor samples revealed overexpression of PRKCI. We confirmed overexpression of PKCι at the mRNA and protein level using our conditional mouse model that authentically recapitulates the progression of Rhabdomyosarcoma in humans. Inhibition of Prkci by RNA interference resulted in a dramatic decrease in anchorage-independent colony formation. Interestingly, treatment of primary cell cultures using aurothiomalate (ATM), which is a gold-containing classical anti-rheumatic agent and a PKCι-specific inhibitor, resulted in decreased interaction between PKCι and Par6, decreased Rac1 activity and reduced cell viability at clinically relevant concentrations. Moreover, co-treatment with ATM and vincristine, a microtubule inhibitor currently used in Rhabdomyosarcoma treatment regimens, resulted in a combination index (C. I.) of 0.470–0.793 through cooperative accumulation of non-proliferative multinuclear cells in the G2/M phase, indicating that these two drugs synergize. For in vivo tumor growth inhibition studies, ATM demonstrated a trend towards enhanced vincristine sensitivity. Overall, these results suggest that PKCι is functionally important in Alveolar Rhabdomyosarcoma anchorage-independent growth and tumor cell proliferation and that combination therapy with ATM and microtubule inhibitors holds promise for the treatment of Alveolar Rhabdomyosarcoma.
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Preclinical Testing of Erlotinib in a Transgenic Alveolar Rhabdomyosarcoma Mouse Model
Sarcoma, 2011Co-Authors: Jinu Abraham, Laura D. Nelon, Courtney B. Kubicek, Aoife Kilcoyne, Sheila T. Hampton, Lee Ann Zarzabal, Francis J. Giles, Joel E. Michalek, Brian P. Rubin, Charles KellerAbstract:Rhabdomyosarcoma is an aggressive childhood malignancy, accounting for more than 50% of all soft-tissue sarcomas in children. Even with extensive therapy, the survival rate among Alveolar Rhabdomyosarcoma patients with advanced disease is only 20%. The receptor tyrosine kinase Epidermal Growth Factor Receptor (EGFR) has been found to be expressed and activated in human Rhabdomyosarcomas. In this study we have used a genetically engineered mouse model for Alveolar Rhabdomyosarcoma (ARMS) which faithfully recapitulates the human disease by activating the pathognomic Pax3:Fkhr fusion gene and inactivating p53 in the maturing myoblasts. We have demonstrated that tumors from our mouse model of Alveolar Rhabdomyosarcoma express EGFR at both the mRNA and protein levels. We then tested the EGFR inhibitor, Erlotinib, for its efficacy in this mouse model of Alveolar Rhabdomyosarcoma. Surprisingly, Erlotinib had no effect on tumor progression, yet mice treated with Erlotinib showed 10–20% loss of body weight. These results suggest that EGFR might not be an a priori monotherapy target in Alveolar Rhabdomyosarcoma.