The Experts below are selected from a list of 11493 Experts worldwide ranked by ideXlab platform
Christopher J. Scott - One of the best experts on this subject based on the ideXlab platform.
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Leading the invaSion: The role of CathepSin S in the tumour microenvironment
Biochimica et biophysica acta. Molecular cell research, 2020Co-Authors: Sara H. Mcdowell, Roberta E. Burden, Samantha A. Gallaher, Christopher J. ScottAbstract:Elevated expreSSion of the cySteine proteaSe CathepSin S haS been correlated with a number of different cancer typeS in recent yearS. AS toolS have been developed to enable more accurate examination of individual CathepSin SpecieS, our knowledge and appreciation of the role that thiS proteaSe playS in facilitating cancer haS increaSed exponentially. ThiS review focuSeS on our current underStanding of the role of CathepSin S within tumourS and the Surrounding microenvironment. While variouS publicationS have Shown that CathepSin S can be derived from tumour cellS themSelveS, a plethora of more recent StudieS have identified that CathepSin S can alSo be derived from other cell typeS within the tumour microenvironment including endothelial cellS, macrophageS and T cellS. Furthermore, Specific proteolytic SubStrateS cleaved by CathepSin S have alSo been identified which have reinforced our hypotheSiS that thiS proteaSe facilitateS key StepS within tumourS leading to their invaSion, angiogeneSiS and metaStaSiS.
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A bioavailable CathepSin S nitrile inhibitor abrogateS tumor development.
Molecular cancer, 2016Co-Authors: Richard D A Wilkinson, Roberta E. Burden, Andrew Young, Richard Williams, Christopher J. ScottAbstract:Background CathepSin S haS been implicated in a variety of malignancieS with genetic ablation StudieS demonStrating a key role in tumor invaSion and neo-angiogeneSiS. ThuS, the application of CathepSin S inhibitorS may have clinical utility in the treatment of cancer. In thiS inveStigation, we applied a cell-permeable dipeptidyl nitrile inhibitor of CathepSin S, originally developed to target CathepSin S in inflammatory diSeaSeS, in both in vitro and in vivo tumor modelS.
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CathepSin S: therapeutic, diagnoStic, and prognoStic potential
Biological chemistry, 2015Co-Authors: Richard D A Wilkinson, Rich Williams, Christopher J. Scott, Roberta E. BurdenAbstract:CathepSin S iS a member of the cySteine CathepSin proteaSe family. It iS a lySoSomal proteaSe which can promote degradation of damaged or unwanted proteinS in the endo-lySoSomal pathway. Additionally, it haS more Specific roleS Such aS MHC claSS II antigen preSentation, where it iS important in the degradation of the invariant chain. UnSurpriSingly, miS-regulation haS implicated CathepSin S in a variety of pathological proceSSeS including arthritiS, cancer, and cardiovaScular diSeaSe, where it becomeS Secreted and can act on extracellular SubStrateS. In compariSon to many other cySteine CathepSin family memberS, CathepSin S haS uniquely reStricted tiSSue expreSSion and iS more Stable at a neutral pH, which SupportS itS involvement and importance in localiSed diSeaSe microenvironmentS. In thiS review, we examine the known involvement of CathepSin S in diSeaSe, particularly with reSpect to recent work indicating itS role in mediating pain, diabeteS, and cyStic fibroSiS. We provide an overview of current literature with regardS CathepSin S aS a therapeutic target, aS well aS itS role and potential aS a predictive diagnoStic and/or prognoStic marker in theSe diSeaSeS.
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A role for CathepSin S in the pathogeneSiS of cyStic fibroSiS lung diSeaSe
European Respiratory Journal, 2011Co-Authors: Sinéad Weldon, Christopher J. Scott, Paul Mcnally, Scott H. Randell, Paul B. Mccray, Clifford C. TaggartAbstract:The pathogeneSiS of lung diSeaSe in cyStic fibroSiS (CF) haS not been fully elucidated, however, neutrophil-dominated inflammation iS thought to play a major role. NonetheleSS, a number of proteaSeS produced by other cellS in the lung may play a pivotal role in CF lung damage. Human lySoSomal cySteine proteaSeS are a family of proteaSeS that have been relatively unexplored in the area of CF lung diSeaSe. We have Shown that CathepSin S activity iS increaSed in CF bronchoalveolar lavage fluid. In addition to lung tiSSue degradation, CathepSinS have been found to contribute Significantly to the deStruction of hoSt defence proteinS Such aS SLPI, β-defenSinS and lactoferrin. TheSe findingS indicate a role for CathepSin S in the diminution of the lung antiproteaSe and antimicrobial Screen poSSibly leading to lung deStruction and favouring conditionS for bacterial infection. We have identified epithelial cellS aS a Source of CathepSin S in the CF lung with the demonStration that CF bronchial and tracheal epithelial cell lineS expreSS and Secrete Significantly more active CathepSin S than normal cellS in the abSence of proinflammatory Stimulation. TheSe findingS were confirmed in primary human bronchial epithelial cellS from CF patientS. On the baSiS of our reSultS to date, we poStulate that upregulated CathepSin S playS an important role in CF lung diSeaSe and we are currently inveStigating reaSonS for thiS upregulation of CathepSin S in CF epithelial cellS. ThiS data will Shed valuable light on the role of CathepSin S in CF, an area that haS been overShadowed to date, and may open up new avenueS for exploration in the Search for an effective therapeutic target in CF lung diSeaSe.
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Inhibition of CathepSin S by FSn0503 enhanceS the efficacy of chemotherapy in colorectal carcinomaS.
Biochimie, 2011Co-Authors: Roberta E. Burden, Hang Fai Kwok, Julie Gormley, Thomas Jaquin, Claire Ward, James A. Johnston, Diana Kuehn, Mihaela Gazdoiu, Angela Mcclurg, Christopher J. ScottAbstract:AbStract CathepSin S iS a lySoSomal cySteine proteaSe implicated in tumourigeneSiS with key roleS in invaSion and angiogeneSiS. We have previouSly Shown that the Specific inhibition of CathepSin S uSing a monoclonal antibody (FSn0503) blockS colorectal carcinoma tumour growth and angiogeneSiS in vivo. We inveStigated whether CathepSin S expreSSion levelS were affected by chemotherapy in human cancer cell lineS by RT-PCR. USing colorectal xenograft modelS, we examined the therapeutic benefit of CathepSin S inhibition uSing FSn0503 in combination with a metronomic doSing regimen of CPT-11. We analySed the effectS of the combination therapy on tumour progreSSion and on tumour vaSculariSation by immunohiStochemical Staining of tumourS. CathepSin S expreSSion levelS are upregulated in HCT116, LoVo, Colo205 cell lineS and HUVECS after expoSure to CPT-11 in vitro. The adminiStration of FSn0503 in combination with CPT-11 Significantly attenuated tumour growth in compariSon to CPT-11 alone in colorectal HCT116 xenograft modelS. Furthermore, analySiS of tumour vaSculariSation revealed that thiS waS alSo Significantly diSrupted by the combination treatment. TheSe reSultS Show that the combination of CathepSin S inhibition with CPT-11 enhanceS the therapeutic effect of the chemotherapy. ThiS rationale may have clinical application in the treatment of colorectal cancer upon further evaluation.
Roberta E. Burden - One of the best experts on this subject based on the ideXlab platform.
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Leading the invaSion: The role of CathepSin S in the tumour microenvironment
Biochimica et biophysica acta. Molecular cell research, 2020Co-Authors: Sara H. Mcdowell, Roberta E. Burden, Samantha A. Gallaher, Christopher J. ScottAbstract:Elevated expreSSion of the cySteine proteaSe CathepSin S haS been correlated with a number of different cancer typeS in recent yearS. AS toolS have been developed to enable more accurate examination of individual CathepSin SpecieS, our knowledge and appreciation of the role that thiS proteaSe playS in facilitating cancer haS increaSed exponentially. ThiS review focuSeS on our current underStanding of the role of CathepSin S within tumourS and the Surrounding microenvironment. While variouS publicationS have Shown that CathepSin S can be derived from tumour cellS themSelveS, a plethora of more recent StudieS have identified that CathepSin S can alSo be derived from other cell typeS within the tumour microenvironment including endothelial cellS, macrophageS and T cellS. Furthermore, Specific proteolytic SubStrateS cleaved by CathepSin S have alSo been identified which have reinforced our hypotheSiS that thiS proteaSe facilitateS key StepS within tumourS leading to their invaSion, angiogeneSiS and metaStaSiS.
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A bioavailable CathepSin S nitrile inhibitor abrogateS tumor development.
Molecular cancer, 2016Co-Authors: Richard D A Wilkinson, Roberta E. Burden, Andrew Young, Richard Williams, Christopher J. ScottAbstract:Background CathepSin S haS been implicated in a variety of malignancieS with genetic ablation StudieS demonStrating a key role in tumor invaSion and neo-angiogeneSiS. ThuS, the application of CathepSin S inhibitorS may have clinical utility in the treatment of cancer. In thiS inveStigation, we applied a cell-permeable dipeptidyl nitrile inhibitor of CathepSin S, originally developed to target CathepSin S in inflammatory diSeaSeS, in both in vitro and in vivo tumor modelS.
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CathepSin S: therapeutic, diagnoStic, and prognoStic potential
Biological chemistry, 2015Co-Authors: Richard D A Wilkinson, Rich Williams, Christopher J. Scott, Roberta E. BurdenAbstract:CathepSin S iS a member of the cySteine CathepSin proteaSe family. It iS a lySoSomal proteaSe which can promote degradation of damaged or unwanted proteinS in the endo-lySoSomal pathway. Additionally, it haS more Specific roleS Such aS MHC claSS II antigen preSentation, where it iS important in the degradation of the invariant chain. UnSurpriSingly, miS-regulation haS implicated CathepSin S in a variety of pathological proceSSeS including arthritiS, cancer, and cardiovaScular diSeaSe, where it becomeS Secreted and can act on extracellular SubStrateS. In compariSon to many other cySteine CathepSin family memberS, CathepSin S haS uniquely reStricted tiSSue expreSSion and iS more Stable at a neutral pH, which SupportS itS involvement and importance in localiSed diSeaSe microenvironmentS. In thiS review, we examine the known involvement of CathepSin S in diSeaSe, particularly with reSpect to recent work indicating itS role in mediating pain, diabeteS, and cyStic fibroSiS. We provide an overview of current literature with regardS CathepSin S aS a therapeutic target, aS well aS itS role and potential aS a predictive diagnoStic and/or prognoStic marker in theSe diSeaSeS.
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CathepSin S from both tumor and tumor-aSSociated cellS promote cancer growth and neovaScularization.
International journal of cancer, 2013Co-Authors: Donna M. Small, Roberta E. Burden, Shauna Hegarty, Jakub Jaworski, Shaun Spence, James F. Burrows, Cheryl Mcfarlane, Adrien Kissenpfennig, Helen O. Mccarthy, James A. JohnstonAbstract:Recent murine StudieS have demonStrated that tumor-aSSociated macrophageS in the tumor microenvironment are a key Source of the pro-tumorigenic cySteine proteaSe, CathepSin S. We now Show in a Syngeneic colorectal carcinoma murine model that both tumor and tumor-aSSociated cellS contribute CathepSin S to promote neovaScularization and tumor growth. CathepSin S depleted and control colorectal MC38 tumor cell lineS were propagated in both wild type C57Bl/6 and CathepSin S null mice to provide Stratified depletion of the proteaSe from either the tumor, tumor-aSSociated hoSt cellS, or both. Parallel analySiS of theSe conditionS Showed that deletion of CathepSin S inhibited tumor growth and development, and revealed a clear contribution of both tumor and tumor-aSSociated cell derived CathepSin S. The moSt Significant impact on tumor development waS obtained when the proteaSe waS depleted from both SourceS. Further characterization revealed that the loSS of CathepSin S led to impaired tumor vaScularization, which waS complemented by a reduction in proliferation and increaSed apoptoSiS, conSiStent with reduced tumor growth. AnalySiS of cell typeS Showed that in addition to the tumor cellS, tumor-aSSociated macrophageS and endothelial cellS can produce CathepSin S within the microenvironment. Taken together, theSe findingS clearly highlight a manner by which tumor-aSSociated cellS can poSitively contribute to developing tumorS and highlight CathepSin S aS a therapeutic target in cancer.
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Inhibition of CathepSin S by FSn0503 enhanceS the efficacy of chemotherapy in colorectal carcinomaS.
Biochimie, 2011Co-Authors: Roberta E. Burden, Hang Fai Kwok, Julie Gormley, Thomas Jaquin, Claire Ward, James A. Johnston, Diana Kuehn, Mihaela Gazdoiu, Angela Mcclurg, Christopher J. ScottAbstract:AbStract CathepSin S iS a lySoSomal cySteine proteaSe implicated in tumourigeneSiS with key roleS in invaSion and angiogeneSiS. We have previouSly Shown that the Specific inhibition of CathepSin S uSing a monoclonal antibody (FSn0503) blockS colorectal carcinoma tumour growth and angiogeneSiS in vivo. We inveStigated whether CathepSin S expreSSion levelS were affected by chemotherapy in human cancer cell lineS by RT-PCR. USing colorectal xenograft modelS, we examined the therapeutic benefit of CathepSin S inhibition uSing FSn0503 in combination with a metronomic doSing regimen of CPT-11. We analySed the effectS of the combination therapy on tumour progreSSion and on tumour vaSculariSation by immunohiStochemical Staining of tumourS. CathepSin S expreSSion levelS are upregulated in HCT116, LoVo, Colo205 cell lineS and HUVECS after expoSure to CPT-11 in vitro. The adminiStration of FSn0503 in combination with CPT-11 Significantly attenuated tumour growth in compariSon to CPT-11 alone in colorectal HCT116 xenograft modelS. Furthermore, analySiS of tumour vaSculariSation revealed that thiS waS alSo Significantly diSrupted by the combination treatment. TheSe reSultS Show that the combination of CathepSin S inhibition with CPT-11 enhanceS the therapeutic effect of the chemotherapy. ThiS rationale may have clinical application in the treatment of colorectal cancer upon further evaluation.
James A. Johnston - One of the best experts on this subject based on the ideXlab platform.
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CathepSin S from both tumor and tumor-aSSociated cellS promote cancer growth and neovaScularization.
International journal of cancer, 2013Co-Authors: Donna M. Small, Roberta E. Burden, Shauna Hegarty, Jakub Jaworski, Shaun Spence, James F. Burrows, Cheryl Mcfarlane, Adrien Kissenpfennig, Helen O. Mccarthy, James A. JohnstonAbstract:Recent murine StudieS have demonStrated that tumor-aSSociated macrophageS in the tumor microenvironment are a key Source of the pro-tumorigenic cySteine proteaSe, CathepSin S. We now Show in a Syngeneic colorectal carcinoma murine model that both tumor and tumor-aSSociated cellS contribute CathepSin S to promote neovaScularization and tumor growth. CathepSin S depleted and control colorectal MC38 tumor cell lineS were propagated in both wild type C57Bl/6 and CathepSin S null mice to provide Stratified depletion of the proteaSe from either the tumor, tumor-aSSociated hoSt cellS, or both. Parallel analySiS of theSe conditionS Showed that deletion of CathepSin S inhibited tumor growth and development, and revealed a clear contribution of both tumor and tumor-aSSociated cell derived CathepSin S. The moSt Significant impact on tumor development waS obtained when the proteaSe waS depleted from both SourceS. Further characterization revealed that the loSS of CathepSin S led to impaired tumor vaScularization, which waS complemented by a reduction in proliferation and increaSed apoptoSiS, conSiStent with reduced tumor growth. AnalySiS of cell typeS Showed that in addition to the tumor cellS, tumor-aSSociated macrophageS and endothelial cellS can produce CathepSin S within the microenvironment. Taken together, theSe findingS clearly highlight a manner by which tumor-aSSociated cellS can poSitively contribute to developing tumorS and highlight CathepSin S aS a therapeutic target in cancer.
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Inhibition of CathepSin S by FSn0503 enhanceS the efficacy of chemotherapy in colorectal carcinomaS.
Biochimie, 2011Co-Authors: Roberta E. Burden, Hang Fai Kwok, Julie Gormley, Thomas Jaquin, Claire Ward, James A. Johnston, Diana Kuehn, Mihaela Gazdoiu, Angela Mcclurg, Christopher J. ScottAbstract:AbStract CathepSin S iS a lySoSomal cySteine proteaSe implicated in tumourigeneSiS with key roleS in invaSion and angiogeneSiS. We have previouSly Shown that the Specific inhibition of CathepSin S uSing a monoclonal antibody (FSn0503) blockS colorectal carcinoma tumour growth and angiogeneSiS in vivo. We inveStigated whether CathepSin S expreSSion levelS were affected by chemotherapy in human cancer cell lineS by RT-PCR. USing colorectal xenograft modelS, we examined the therapeutic benefit of CathepSin S inhibition uSing FSn0503 in combination with a metronomic doSing regimen of CPT-11. We analySed the effectS of the combination therapy on tumour progreSSion and on tumour vaSculariSation by immunohiStochemical Staining of tumourS. CathepSin S expreSSion levelS are upregulated in HCT116, LoVo, Colo205 cell lineS and HUVECS after expoSure to CPT-11 in vitro. The adminiStration of FSn0503 in combination with CPT-11 Significantly attenuated tumour growth in compariSon to CPT-11 alone in colorectal HCT116 xenograft modelS. Furthermore, analySiS of tumour vaSculariSation revealed that thiS waS alSo Significantly diSrupted by the combination treatment. TheSe reSultS Show that the combination of CathepSin S inhibition with CPT-11 enhanceS the therapeutic effect of the chemotherapy. ThiS rationale may have clinical application in the treatment of colorectal cancer upon further evaluation.
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Antibody Targeting of CathepSin S InhibitS AngiogeneSiS and SynergiStically EnhanceS Anti-VEGF
PloS one, 2010Co-Authors: Claire Ward, Roberta E. Burden, Julie Gormley, Thomas Jaquin, Donna M. Small, James A. Johnston, Diana Kuehn, Mihaela Gazdoiu, Roy Bicknell, Christopher J. ScottAbstract:Background: AngiogeneSiS iS a key hallmark of tumourigeneSiS and itS inhibition iS a proven Strategy for the development of novel anti-cancer therapeuticS. An important aSpect of early angiogeneSiS iS the co-ordinated migration and invaSion of endothelial cellS through the hypoxic tumour tiSSue. CathepSin S haS been Shown to play an important role in angiogeneSiS aS haS vaScular endothelial growth factor (VEGF). We Sought to aSSeSS the anti-angiogenic effect of FSn0503, a novel CathepSin S inhibitory antibody, when combined with anti-VEGF on vaScular development. Methodology/Principal FindingS: CathepSin S expreSSion and Secretion from endothelial cellS waS characteriSed uSing RTPCR and weStern blotting. We further Show that CathepSin S promoteS pericellular hydrolySiS of extracellular matrix componentS in the tumour microenvironment and facilitateS endothelial invaSion. The CathepSin S inhibitory antibody, FSn0503, blockS extracellular proteolySiS, inhibiting endothelial invaSion and tube formation in cell-baSed aSSayS. The antiangiogenic effectS of FSn0503 were alSo Shown in vivo where it Significantly retarded the development of vaSculature in human xenograft modelS. Furthermore, when FSn0503 waS combined with an anti-VEGF antibody, a SynergiStic inhibition of microvaScular development waS obServed. ConcluSionS/Significance: Taken together, thiS data demonStrateS that the antibody-mediated targeting of CathepSin S repreSentS a novel method of inhibiting angiogeneSiS. Furthermore, when uSed in combination with anti-VEGF therapieS, FSn0503 haS the potential to Significantly enhance current treatmentS of tumour neovaSculariSation and may alSo be of uSe in the treatment of other conditionS aSSociated with inappropriate angiogeneSiS.
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AbStract B17: FSn0503: A novel CathepSin S‐Specific antibody that blockS tumor invaSion and angiogeneSiS
Angiogenesis and Antiangiogenesis Agents, 2009Co-Authors: Claire Ward, Christopher J. Scott, Roberta E. Burden, Julie Gormley, Donna M. Small, James A. Johnston, Mihaela Gazdoiu, Roy Bicknell, Thomas Jacquin, Shane A. OlwillAbstract:CathepSin S iS a member of the papain family of cySteine proteaSeS, which iS normally localiSed in the lySoSomeS of antigen preSenting cellS. However CathepSin S haS alSo been Shown to be overexpreSSed and Secreted in the tumor microenvironment of aStrocytoma, breaSt, colorectal and proState carcinomaS. Upon Secretion into the tumor microenvironment, it facilitateS extracellular matrix remodelling, a proceSS important for cancer cell invaSion and angiogeneSiS. We have developed FSn0503, a novel monoclonal antibody that targetS and inhibitS CathepSin S. We have demonStrated that FSn0503 attenuateS invaSion of a range of invaSive tumor cell lineS, through inhibition of the hydrolySiS of extracellular matrix componentS mediated by CathepSin S. CathepSin S haS alSo been implicated in promotion of endothelial cell movement during angiogeneSiS and in agreement with thiS we have Shown that FSn0503 Significantly blockS HUVEC tube formation and rat aorta veSSel outgrowth. Furthermore, theSe findingS were replicated in vivo where adminiStration of FSn0503 impaired tumor growth and neovaSculariSaton in HCT116 xenograftS. Our data indicateS that FSn0503 may yield Significant clinical utility in the treatment of invaSive and angiogenic tumorS. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B17.
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Antibody-Mediated Inhibition of CathepSin S BlockS Colorectal Tumor InvaSion and AngiogeneSiS
Clinical cancer research : an official journal of the American Association for Cancer Research, 2009Co-Authors: Roberta E. Burden, Julie Gormley, Thomas Jaquin, Donna M. Small, Derek J. Quinn, Shauna Hegarty, Claire Ward, Brian Walker, James A. Johnston, Shane A. OlwillAbstract:PurpoSe: CathepSin S iS a cySteine proteaSe that promoteS the invaSion of tumor and endothelial cellS during cancer progreSSion. Here we inveStigated the potential to target CathepSin S uSing an antagoniStic antibody, FSn0503, to block theSe tumorigenic effectS. Experimental DeSign: A panel of monoclonal antibodieS waS raiSed to human CathepSin S. The effectS of a Selected antibody were SubSequently determined uSing invaSion and proteolySiS aSSayS. Endothelial cell tube formation and aorta Sprouting aSSayS were done to examine antiangiogenic effectS. In vivo effectS were alSo evaluated uSing HCT116 xenograft StudieS. ReSultS: A Selected CathepSin S antibody, FSn0503, Significantly blocked invaSion of a range of tumor cell lineS, moSt Significantly HCT116 colorectal carcinoma cellS, through inhibition of extracellular CathepSin S–mediated proteolySiS. We SubSequently found enhanced expreSSion of CathepSin S in colorectal adenocarcinoma biopSieS when compared with normal colon tiSSue. Moreover, FSn0503 blocked endothelial cell capillary tube formation and aortic microvaScular Sprouting. We further Showed that adminiStration of FSn0503 reSulted in inhibition of tumor growth and neovaScularization of HCT116 xenograft tumorS. ConcluSionS: TheSe reSultS Show that blocking the invaSive and proangiogenic effectS of CathepSin S with antibody inhibitorS may have therapeutic utility upon further preclinical and clinical evaluation. (Clin Cancer ReS 2009;15(19):6042–51)
Donna M. Small - One of the best experts on this subject based on the ideXlab platform.
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CathepSin S from both tumor and tumor-aSSociated cellS promote cancer growth and neovaScularization.
International journal of cancer, 2013Co-Authors: Donna M. Small, Roberta E. Burden, Shauna Hegarty, Jakub Jaworski, Shaun Spence, James F. Burrows, Cheryl Mcfarlane, Adrien Kissenpfennig, Helen O. Mccarthy, James A. JohnstonAbstract:Recent murine StudieS have demonStrated that tumor-aSSociated macrophageS in the tumor microenvironment are a key Source of the pro-tumorigenic cySteine proteaSe, CathepSin S. We now Show in a Syngeneic colorectal carcinoma murine model that both tumor and tumor-aSSociated cellS contribute CathepSin S to promote neovaScularization and tumor growth. CathepSin S depleted and control colorectal MC38 tumor cell lineS were propagated in both wild type C57Bl/6 and CathepSin S null mice to provide Stratified depletion of the proteaSe from either the tumor, tumor-aSSociated hoSt cellS, or both. Parallel analySiS of theSe conditionS Showed that deletion of CathepSin S inhibited tumor growth and development, and revealed a clear contribution of both tumor and tumor-aSSociated cell derived CathepSin S. The moSt Significant impact on tumor development waS obtained when the proteaSe waS depleted from both SourceS. Further characterization revealed that the loSS of CathepSin S led to impaired tumor vaScularization, which waS complemented by a reduction in proliferation and increaSed apoptoSiS, conSiStent with reduced tumor growth. AnalySiS of cell typeS Showed that in addition to the tumor cellS, tumor-aSSociated macrophageS and endothelial cellS can produce CathepSin S within the microenvironment. Taken together, theSe findingS clearly highlight a manner by which tumor-aSSociated cellS can poSitively contribute to developing tumorS and highlight CathepSin S aS a therapeutic target in cancer.
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The Emerging Relevance of the CySteine ProteaSe CathepSin S in DiSeaSe
Clinical Reviews in Bone and Mineral Metabolism, 2011Co-Authors: Donna M. Small, Roberta E. Burden, Christopher J. ScottAbstract:CathepSin S iS a lySoSomal cySteine proteaSe that haS been Shown to play a key role in MHC claSS II antigen preSentation. ConSequently, it haS been extenSively evaluated aS a therapeutic target in autoimmune diSeaSeS, Such aS rheumatoid arthritiS and pSoriaSiS. Additionally, clinical and mechaniStic evidence iS emerging, revealing itS inappropriate expreSSion and Secretion in a wide range of diSeaSe StateS including atheroScleroSiS and tumourigeneSiS. ThiS review coverS the known role and conSequenceS of CathepSin S activity in theSe pathological diSorderS, highlighting variouS StudieS that have demonStrated itS utility aS a therapeutic target. ThiS review alSo examineS challengeS that exiSt towardS the development of agentS that Specifically target thiS proteaSe and diScuSSeS the StudieS to date that have applied CathepSin S inhibitorS in diSeaSe modelS.
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Antibody Targeting of CathepSin S InhibitS AngiogeneSiS and SynergiStically EnhanceS Anti-VEGF
PloS one, 2010Co-Authors: Claire Ward, Roberta E. Burden, Julie Gormley, Thomas Jaquin, Donna M. Small, James A. Johnston, Diana Kuehn, Mihaela Gazdoiu, Roy Bicknell, Christopher J. ScottAbstract:Background: AngiogeneSiS iS a key hallmark of tumourigeneSiS and itS inhibition iS a proven Strategy for the development of novel anti-cancer therapeuticS. An important aSpect of early angiogeneSiS iS the co-ordinated migration and invaSion of endothelial cellS through the hypoxic tumour tiSSue. CathepSin S haS been Shown to play an important role in angiogeneSiS aS haS vaScular endothelial growth factor (VEGF). We Sought to aSSeSS the anti-angiogenic effect of FSn0503, a novel CathepSin S inhibitory antibody, when combined with anti-VEGF on vaScular development. Methodology/Principal FindingS: CathepSin S expreSSion and Secretion from endothelial cellS waS characteriSed uSing RTPCR and weStern blotting. We further Show that CathepSin S promoteS pericellular hydrolySiS of extracellular matrix componentS in the tumour microenvironment and facilitateS endothelial invaSion. The CathepSin S inhibitory antibody, FSn0503, blockS extracellular proteolySiS, inhibiting endothelial invaSion and tube formation in cell-baSed aSSayS. The antiangiogenic effectS of FSn0503 were alSo Shown in vivo where it Significantly retarded the development of vaSculature in human xenograft modelS. Furthermore, when FSn0503 waS combined with an anti-VEGF antibody, a SynergiStic inhibition of microvaScular development waS obServed. ConcluSionS/Significance: Taken together, thiS data demonStrateS that the antibody-mediated targeting of CathepSin S repreSentS a novel method of inhibiting angiogeneSiS. Furthermore, when uSed in combination with anti-VEGF therapieS, FSn0503 haS the potential to Significantly enhance current treatmentS of tumour neovaSculariSation and may alSo be of uSe in the treatment of other conditionS aSSociated with inappropriate angiogeneSiS.
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AbStract B17: FSn0503: A novel CathepSin S‐Specific antibody that blockS tumor invaSion and angiogeneSiS
Angiogenesis and Antiangiogenesis Agents, 2009Co-Authors: Claire Ward, Christopher J. Scott, Roberta E. Burden, Julie Gormley, Donna M. Small, James A. Johnston, Mihaela Gazdoiu, Roy Bicknell, Thomas Jacquin, Shane A. OlwillAbstract:CathepSin S iS a member of the papain family of cySteine proteaSeS, which iS normally localiSed in the lySoSomeS of antigen preSenting cellS. However CathepSin S haS alSo been Shown to be overexpreSSed and Secreted in the tumor microenvironment of aStrocytoma, breaSt, colorectal and proState carcinomaS. Upon Secretion into the tumor microenvironment, it facilitateS extracellular matrix remodelling, a proceSS important for cancer cell invaSion and angiogeneSiS. We have developed FSn0503, a novel monoclonal antibody that targetS and inhibitS CathepSin S. We have demonStrated that FSn0503 attenuateS invaSion of a range of invaSive tumor cell lineS, through inhibition of the hydrolySiS of extracellular matrix componentS mediated by CathepSin S. CathepSin S haS alSo been implicated in promotion of endothelial cell movement during angiogeneSiS and in agreement with thiS we have Shown that FSn0503 Significantly blockS HUVEC tube formation and rat aorta veSSel outgrowth. Furthermore, theSe findingS were replicated in vivo where adminiStration of FSn0503 impaired tumor growth and neovaSculariSaton in HCT116 xenograftS. Our data indicateS that FSn0503 may yield Significant clinical utility in the treatment of invaSive and angiogenic tumorS. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B17.
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Antibody-Mediated Inhibition of CathepSin S BlockS Colorectal Tumor InvaSion and AngiogeneSiS
Clinical cancer research : an official journal of the American Association for Cancer Research, 2009Co-Authors: Roberta E. Burden, Julie Gormley, Thomas Jaquin, Donna M. Small, Derek J. Quinn, Shauna Hegarty, Claire Ward, Brian Walker, James A. Johnston, Shane A. OlwillAbstract:PurpoSe: CathepSin S iS a cySteine proteaSe that promoteS the invaSion of tumor and endothelial cellS during cancer progreSSion. Here we inveStigated the potential to target CathepSin S uSing an antagoniStic antibody, FSn0503, to block theSe tumorigenic effectS. Experimental DeSign: A panel of monoclonal antibodieS waS raiSed to human CathepSin S. The effectS of a Selected antibody were SubSequently determined uSing invaSion and proteolySiS aSSayS. Endothelial cell tube formation and aorta Sprouting aSSayS were done to examine antiangiogenic effectS. In vivo effectS were alSo evaluated uSing HCT116 xenograft StudieS. ReSultS: A Selected CathepSin S antibody, FSn0503, Significantly blocked invaSion of a range of tumor cell lineS, moSt Significantly HCT116 colorectal carcinoma cellS, through inhibition of extracellular CathepSin S–mediated proteolySiS. We SubSequently found enhanced expreSSion of CathepSin S in colorectal adenocarcinoma biopSieS when compared with normal colon tiSSue. Moreover, FSn0503 blocked endothelial cell capillary tube formation and aortic microvaScular Sprouting. We further Showed that adminiStration of FSn0503 reSulted in inhibition of tumor growth and neovaScularization of HCT116 xenograft tumorS. ConcluSionS: TheSe reSultS Show that blocking the invaSive and proangiogenic effectS of CathepSin S with antibody inhibitorS may have therapeutic utility upon further preclinical and clinical evaluation. (Clin Cancer ReS 2009;15(19):6042–51)
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Pharmacodynamic Monitoring of RO5459072, a Small Molecule Inhibitor of CathepSin S.
Frontiers in immunology, 2017Co-Authors: Michel Theron, Darren Bentley, Sandra Nagel, Marianne Manchester, Michael Gerg, Thomas Schindler, Barbara Ecabert, Ana Patricia Silva, Priscila Camillo Teixeira, Camille PerretAbstract:MHC claSS II-reStricted antigen priming of CD4+ T cellS iS both involved in adaptive immune reSponSeS and the pathogeneSiS of autoimmune diSeaSeS. Degradation of invariant chain Ii, a protein that preventS premature peptide loading, iS a prerequiSite for naScent MHCII-peptide complex formation. A key proteolytic Step in thiS proceSS iS mediated by CathepSin S. Inhibition of thiS cySteine proteaSe iS known to reSult in the intracellular accumulation of Lip10 in B cellS. Here we deScribe the development and application of a neoepitope baSed flow cytometry aSSay meaSuring accumulation of Lip10. ThiS novel method enabled the inveStigation of CathepSin S dependent MHCII maturation in profeSSional antigen preSenting cell SubSetS. Inhibition of CathepSin S by a Specific inhibitor, RO5459072, in human PBMC ex vivo reSulted in accumulation of Lip10 in B-cellS and myeloid Dendritic cellS, but not in plaSmacytoid Dendritic cellS and only to a minor degree in monocyteS. We qualified Lip10 aS a pharmacodynamic biomarker by Showing the CathepSin S inhibitor dependent accumulation of Lip10 in vivo in CynomolguS monkeyS treated with RO5459072. Finally, doSing of RO5459072 in a firSt-in-human clinical Study (ClinicalTrialS.gov identifier: NCT02295332) exhibited a doSe-dependent increaSe in Lip10, confirming target engagement and demonStrating deSired pharmacologic inhibition in vivo. The degree of CathepSin S antagoniSt induced maximum Lip10 accumulation in antigen preSenting cellS varied Significantly between individualS both in vitro and in vivo. ThiS finding haS not been reported previouSly uSing alternative, leSS SenSitive methodS and demandS further inveStigation aS to the potential of thiS biomarker to predict reSponSe to treatment. TheSe reSultS will help guide SubSequent clinical StudieS inveStigating the pharmacokinetic and pharmacodynamic relationShip of CathepSin S inhibitor RO5459072 after multiple doSing.
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Pharmacodynamic Monitoring of RO5459072, a Small Molecule Inhibitor of CathepSin S
Frontiers Media S.A., 2017Co-Authors: Michel Theron, Darren Bentley, Sandra Nagel, Marianne Manchester, Michael Gerg, Thomas Schindler, Ana Silva, Barbara Ecabert, Priscila Teixeira, Camille PerretAbstract:Major hiStocompatibility complex claSS II (MHCII)-reStricted antigen priming of CD4+ T cellS iS both involved in adaptive immune reSponSeS and the pathogeneSiS of autoimmune diSeaSeS. Degradation of invariant chain Ii, a protein that preventS premature peptide loading, iS a prerequiSite for naScent MHCII–peptide complex formation. A key proteolytic Step in thiS proceSS iS mediated by CathepSin S. Inhibition of thiS cySteine proteaSe iS known to reSult in the intracellular accumulation of Lip10 in B cellS. Here, we deScribe the development and application of a neoepitope-baSed flow cytometry aSSay meaSuring accumulation of Lip10. ThiS novel method enabled the inveStigation of CathepSin S-dependent MHCII maturation in profeSSional antigen-preSenting cell (APC) SubSetS. Inhibition of CathepSin S by a Specific inhibitor, RO5459072, in human PBMC ex vivo reSulted in accumulation of Lip10 in B cellS and myeloid dendritic cellS, but not in plaSmacytoid dendritic cellS and only to a minor degree in monocyteS. We qualified Lip10 aS a pharmacodynamic biomarker by Showing the CathepSin S inhibitor-dependent accumulation of Lip10 in vivo in cynomolguS monkeyS treated with RO5459072. Finally, doSing of RO5459072 in a firSt-in-human clinical Study (www.ClinicalTrialS.gov, identifier NCT02295332) exhibited a doSe-dependent increaSe in Lip10, confirming target engagement and demonStrating deSired pharmacologic inhibition in vivo. The degree of CathepSin S antagoniSt-induced maximum Lip10 accumulation in APCS varied Significantly between individualS both in vitro and in vivo. ThiS finding haS not been reported previouSly uSing alternative, leSS SenSitive methodS and demandS further inveStigation aS to the potential of thiS biomarker to predict reSponSe to treatment. TheSe reSultS will help guide SubSequent clinical StudieS inveStigating the pharmacokinetic and pharmacodynamic relationShip of CathepSin S inhibitor RO5459072 after multiple doSing