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Anna Bagnato - One of the best experts on this subject based on the ideXlab platform.

  • TherApeutics, TArgets, And ChemicAl Biology Endothelin A Receptor/b-Arrestin SignAling to the Wnt PAthwAy Renders OvAriAn CAncer Cells ResistAnt to
    2016
    Co-Authors: Roberta Cianfrocca, Piera Tocci, Valentina Caprara, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, Elisa Semprucci, Gabriella Ferr, Anna Bagnato
    Abstract:

    The high mortAlity of epitheliAl ovAriAn cAncer (EOC) is mAinly cAused by resistAnce to the AvAilAble therApies. In EOC, the Endothelin-1 (ET-1, EDN1)–Endothelin A Receptor (ETAR, EDNRA) signAling Axis regulAtes the epitheliAl–mesenchymAl trAnsition (EMT) And A chemoresistAnt phenotype. However, there is A pAucity of knowledge About how ET-1 mediAtes drug resistAnce. Here, we define A novel bypAss mechAnism through which ETAR/b-Arrestin-1 (b-Arr1, ARRB1) links Wnt signAling to Acquire chemoresistAnt And EMT phenotype. We found thAt ETAR/b-Arr1 Activity promoted nucleAr complex with b-cAtenin And p300, resulting in histone AcetylAtion, chromAtin reorgAnizAtion, And enhAnced trAnscription of genes, such As ET-1, enhAncing the network thAt sustAins chemoresistAnce. Silencing of b-Arr1 or phArmAcologic treAtment with the duAl ETAR/ETBR AntAgonist mAcitentAn prevented core complex formAtion And restored drug sensitivity, impAiring the signAling pAthwAys involved in cell survivAl, EMT, And invAsion. In vivo mAcitentAn treAtment reduced tumor growth, vAsculArizAtion, intrAvAsAtion, And metAstAtic progression. The combinAtion of mAcitentAn And cisplAtinum resulted in the potentiAtion of the cytotoxic effect, indicAting thAt mAcitentAn cAn enhAnce sensitivity to chemotherApy. InvestigAtions in clinicAl specimens of chemoresistAnt EOC tissues confirmed increAsed recruitment of b-Arr1 And b-cAtenin to ET-1 gene promoter. In these tissues, high expression of ETAR significAntly AssociAted with poor clinicAl outcome And chemoresistAnce. Collectively, our findings reveAl the existence of A novel mechAnism by which ETAR/b-Arr1 signAling is integrAted with the Wnt/b-cAtenin pAthwAy to sustAin chemoresistAnce in EOC, And they offer A solid rAtionAle for clinicAl evAluAtion of mAcitentAn in combinAtion with chemotherApy to overcome chemoresistAnce in this setting. CAncer Res; 74(24); 1–12. 2014 AACR

  • Endothelin A Receptor drives invAdopodiA function And cell motility through the β Arrestin pdz rhogef pAthwAy in ovAriAn cArcinomA
    Oncogene, 2016
    Co-Authors: Elisa Semprucci, Piera Tocci, Valentina Caprara, Roberta Cianfrocca, Rosanna Sestito, Gabriella Ferrandina, V Di Castro, M Veglione, Francesca Spadaro, Anna Bagnato
    Abstract:

    The Endothelin-1 (ET-1)/ET A Receptor (ETAR) signAlling pAthwAy is A well-estAblished driver of epitheliAl ovAriAn cAncer (EOC) progression. One key process promoted by ET-1 is tumor cell invAsion, which requires the scAffolding functions of β-Arrestin-1 (β-Arr1) downstreAm of the Receptor; however, the potentiAl role of ET-1 in inducing invAdopodiA, which Are cruciAl for cellulAr invAsion And tumor metAstAsis, is completely unknown. We describe here thAt ET-1/ETAR, through β-Arr1, ActivAtes RhoA And RhoC GTPAse And downstreAm ROCK (Rho-AssociAted coiled coil-forming kinAse) kinAse Activity, promoting Actin-bAsed dynAmic remodelling And enhAnced cell invAsion. This is Accomplished by the direct interAction of β-Arr1 with PDZ-RhoGEF (postsynAptic density protein 95/disc-lArge/zonulA occludens-RhoGEF). Interestingly, ETAR-mediAted invAsive properties Are relAted to the regulAtion of invAdopodiA, As evAluAted by colocAlizAtion of Actin with cortActin, As well As with TKS5 And MT1-MMP (membrAne type 1-mAtrix metAlloproteinAse) with AreAs of mAtrix degrAdAtion, And ActivAtion of cofilin pAthwAy, which is cruciAl for regulAting invAdopodiA Activity. Depletion of PDZ-RhoGEF, or β-Arr1, or RhoC, As well As the treAtment with the duAl ET-1 Receptor AntAgonist mAcitentAn, significAntly impAirs invAdopodiA function, MMP Activity And invAsion, demonstrAting thAt β-Arr1/PDZ-RhoGEF interAction mediAtes ETAR-driven ROCK-LIMK-cofilin pAthwAy through the control of RhoC Activity. In vivo, mAcitentAn is Able to inhibit metAstAtic disseminAtion And cofilin phosphorylAtion. Collectively, our dAtA unveil A noncAnonicAl ActivAtion of the RhoC/ROCK pAthwAy through the β-Arr1/PDZ-RhoGEF complex As A regulAtor of ETAR-induced motility And metAstAsis, estAblishing ET-1 Axis As A novel regulAtor of invAdopodiA protrusions through the RhoC/ROCK/LIMK/cofilin pAthwAy during the initiAl steps of EOC invAsion.

  • Endothelin-1/Endothelin A Receptor Axis ActivAtes RhoA GTPAse in epitheliAl ovAriAn cAncer
    Life Sciences, 2016
    Co-Authors: Piera Tocci, Valentina Caprara, Roberta Cianfrocca, Rosanna Sestito, Valeriana Di Castro, Anna Bagnato, Laura Rosano
    Abstract:

    Aims The Endothelin-1 (ET-1)/ET A Receptor (ETAR) signAling pAthwAy is criticAl driver of epitheliAl ovAriAn cAncer (EOC) progression. Emerging evidences demonstrAte thAt the scAffolding protein β-Arrestin-1 (β-Arr1) downstreAm of ETAR guides cell motility, Although the signAling pAthwAys by which ETAR ActivAtion controls these process Are not well understood. Here, we set out to moleculArly dissect whether RhoA GTPAse ActivAtion is A mediAtor of ET-1 signAling controlling EOC cell migrAtion. MAin methods We cultured EOC cell lines (HEY, SKOV3, OVCAR, A2780 And 2008) with ET-1 And the ET-1R AntAgonist mAcitentAn. RhoA expression wAs evAluAted by RT-PCR. ActivAtion of RhoA And ROCK1 wAs evAluAted by pull down And kinAse AssAys, respectively. Cell motility wAs evAluAted by chemotAxis And wound heAling AssAys, in untrAsfected cells by using ROCK chemicAl inhibitors, Y-27632 or FAsudil, or in cells After trAnsfection with dominAnt negAtive RhoA construct. The phosphorylAtion of myosin light chAin 2 (MLC2) wAs evAluAted by immunoblotting. PseudopodiA formAtion wAs evAluAted by A pseudopodiA kit AssAy. Key findings In EOC cells, ET-1 ActivAtes RhoA And downstreAm ROCK1 And MLC2. These effects were inhibited by β-Arr1 silencing, suggesting thAt ET-1/ETAR regulAte RhoA signAling through β-Arr1. At functionAl level, the ActivAtion of RhoA/ROCK signAling led to enhAnced cell migrAtion And pseudopodiA formAtion. The suppressive effect of the ROCK inhibitors, As well As of mAcitentAn, demonstrAtes thAt RhoA is involved in ET-1/ETAR-induced cell migrAtion. SignificAnce Altogether these findings reveAl A new pAthwAy thAt depends on β-Arr1 to sustAin RhoA/ROCK signAling in response to ETAR ActivAtion in EOC.

  • Endothelin A Receptor β Arrestin signAling to the wnt pAthwAy renders ovAriAn cAncer cells resistAnt to chemotherApy
    Cancer Research, 2014
    Co-Authors: Laura Rosano, Piera Tocci, Valentina Caprara, Roberta Cianfrocca, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, Elisa Semprucci, Gabriella Ferrandina, Anna Bagnato
    Abstract:

    The high mortAlity of epitheliAl ovAriAn cAncer (EOC) is mAinly cAused by resistAnce to the AvAilAble therApies. In EOC, the Endothelin-1 (ET-1, EDN1)-Endothelin A Receptor (ETAR, EDNRA) signAling Axis regulAtes the epitheliAl-mesenchymAl trAnsition (EMT) And A chemoresistAnt phenotype. However, there is A pAucity of knowledge About how ET-1 mediAtes drug resistAnce. Here, we define A novel bypAss mechAnism through which ETAR/β-Arrestin-1 (β-Arr1, ARRB1) links Wnt signAling to Acquire chemoresistAnt And EMT phenotype. We found thAt ETAR/β-Arr1 Activity promoted nucleAr complex with β-cAtenin And p300, resulting in histone AcetylAtion, chromAtin reorgAnizAtion, And enhAnced trAnscription of genes, such As ET-1, enhAncing the network thAt sustAins chemoresistAnce. Silencing of β-Arr1 or phArmAcologic treAtment with the duAl ETAR/ETBR AntAgonist mAcitentAn prevented core complex formAtion And restored drug sensitivity, impAiring the signAling pAthwAys involved in cell survivAl, EMT, And invAsion. In vivo mAcitentAn treAtment reduced tumor growth, vAsculArizAtion, intrAvAsAtion, And metAstAtic progression. The combinAtion of mAcitentAn And cisplAtinum resulted in the potentiAtion of the cytotoxic effect, indicAting thAt mAcitentAn cAn enhAnce sensitivity to chemotherApy. InvestigAtions in clinicAl specimens of chemoresistAnt EOC tissues confirmed increAsed recruitment of β-Arr1 And β-cAtenin to ET-1 gene promoter. In these tissues, high expression of ETAR significAntly AssociAted with poor clinicAl outcome And chemoresistAnce. Collectively, our findings reveAl the existence of A novel mechAnism by which ETAR/β-Arr1 signAling is integrAted with the Wnt/β-cAtenin pAthwAy to sustAin chemoresistAnce in EOC, And they offer A solid rAtionAle for clinicAl evAluAtion of mAcitentAn in combinAtion with chemotherApy to overcome chemoresistAnce in this setting.

  • Acquisition of chemoresistAnce And emt phenotype is linked with ActivAtion of the Endothelin A Receptor pAthwAy in ovAriAn cArcinomA cells
    Clinical Cancer Research, 2011
    Co-Authors: Laura Rosano, Roberta Cianfrocca, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, Maria Rita Nicotra, Gabriella Ferrandina, Alessandro Lucidi, Anna Bagnato
    Abstract:

    Purpose: Emerging evidence suggests moleculAr And phenotypic AssociAtion between chemoresistAnce And epitheliAl–mesenchymAl trAnsition (EMT) in cAncer. Endothelin-1 (ET-1)/Endothelin A Receptor (ET A R) Axis is implicAted in the pAthobiology of epitheliAl ovAriAn cAncer (EOC) by driving tumor-promoting effects, including EMT. Here, we AnAlyzed how ET A R regulAtes chemoresistAnce And EMT in EOC. ExperimentAl Design: The effects of ET-1 Axis on cell proliferAtion, drug-induced Apoptosis, invAsiveness, And EMT were AnAlyzed in cultured EOC cells sensitive And resistAnt to cisplAtinum And tAxol. Tumor growth in response to ET A R AntAgonist wAs exAmined in EOC xenogrAfts. ET A R expression wAs exAmined in 60 humAn EOC tumors by immunohistochemistry And correlAted with chemoresistAnce And EMT. Results: In resistAnt EOC cells ET-1 And ET A R Are upregulAted, pArAlleled by enhAnced mitogen ActivAted protein kinAse (MAPK) And Akt phosphorylAtion And cell proliferAtion. Moreover, in these cells the expression of E-cAdherin trAnscriptionAl repressors, including SnAil, Slug, And Twist, As well As of mesenchymAl mArkers, such As vimentin And N-cAdherin, were upregulAted And linked with enhAnced invAsive behAvior. Interestingly, ET A R blockAde with zibotentAn, A specific ET A R AntAgonist, or its silencing, downregulAted SnAil Activity, restored drug sensitivity to cytotoxic-induced Apoptosis, And inhibited the invAsiveness of resistAnt cells. In vivo , zibotentAn inhibited tumor growth of sensitive And resistAnt EOC xenogrAfts, And sensitized to chemotherApy. AnAlysis of EOC humAn tissues reveAled thAt ET A R is overexpressed in resistAnt tumors And is AssociAted with EMT phenotype. Conclusions: Our dAtA provide the first evidence thAt blockAde of ET A R-driven EMT cAn overcome chemoresistAnce And inhibit tumor progression, improving the outcome of EOC pAtients9 treAtment. Clin CAncer Res; 17(8); 2350–60. ©2011 AACR .

Laura Rosano - One of the best experts on this subject based on the ideXlab platform.

  • β Arrestin1 yAp mutAnt p53 complexes orchestrAte the Endothelin A Receptor signAling in high grAde serous ovAriAn cAncer
    Nature Communications, 2019
    Co-Authors: Piera Tocci, Roberta Cianfrocca, Laura Rosano, Valeriana Di Castro, Andrea Sacconi, Sara Donzelli, Silvia Bonfiglio, Gabriele Bucci, Enrico Vizza, Gabriella Ferrandina
    Abstract:

    The limited clinicAl response observed in high-grAde serous ovAriAn cAncer (HG-SOC) with high frequency of TP53 mutAtions (mutp53) might be relAted to mutp53-driven oncogenic pAthwAy network. Here we show thAt β-Arrestin1 (β-Arr1), interActs with YAP, triggering its cytoplAsmic-nucleAr shuttling. This interAction Allows β-Arr1 to recruit mutp53 to the YAP-TEAD trAnscriptionAl complex upon ActivAtion of Endothelin-1 Receptors (ET-1R) in pAtient-derived HG-SOC cells And in cell lines beAring mutp53. In pArAllel, β-Arr1 mediAtes the ET-1R-induced Trio/RhoA-dependent YAP nucleAr AccumulAtion. In the nucleus, ET-1 through β-Arr1 orchestrAtes the tethering of YAP And mutp53 to YAP/mutp53 tArget gene promoters, including EDN1 thAt ensures persistent signAls. TreAtment of pAtient-derived xenogrAfts reveAls synergistic AntitumorAl And AntimetAstAtic effects of the duAl ET-1R AntAgonist mAcitentAn in combinAtion with cisplAtinum, shutting-down the β-Arr1-mediAted YAP/mutp53 trAnscriptionAl progrAmme. Furthermore, ETAR/β-Arr1/YAP gene signAture correlAtes with A worst prognosis in HG-SOC. These findings support effective combinAtoriAl treAtment for repurposing the ET-1R AntAgonists in HG-SOC. YAP And mutAnt p53 crosstAlk to regulAte trAnscriptionAl processes in cAncers. Here, the Authors show thAt Endothelin-1 mediAted ActivAtion of β-Arrestin interActs with YAP to recruit mutAnt p53 to the TEAD/YAP complex to promote metAstAsis And chemoresistAnce in ovAriAn cAncer.

  • mir 30A inhibits Endothelin A Receptor And chemoresistAnce in ovAriAn cArcinomA
    Oncotarget, 2016
    Co-Authors: Rosanna Sestito, Piera Tocci, Valentina Caprara, Roberta Cianfrocca, Laura Rosano, Valeriana Di Castro, Elisa Semprucci, Gabriella Ferrandina, Andrea Sacconi, Giovanni Blandino
    Abstract:

    Drug resistAnce remAins the mAjor clinicAl bArrier to successful treAtment in epitheliAl ovAriAn cArcinomA (EOC) pAtients, And the evidence of microRNA involvement in drug resistAnce hAs been recently emerging. Endothelin-1 (ET-1)/ETA Receptor (ETAR) Axis is AberrAntly ActivAted in chemoresistAnt EOC cells And elicits pleiotropic effects promoting epitheliAl-to-mesenchymAl trAnsition (EMT) And the Acquisition of chemoresistAnce. However, the relAtionship between ETAR And miRNA is still unknown. Hence, in this study we evAluAted whether dysregulAtion of miRNA might enhAnce ETAR expression in sensitive And resistAnt EOC cells. BAsed on bioinformAtic tools, we selected putAtive miRNA Able to recognize the 3'UTR of ETAR. An inverse correlAtion wAs observed between the expression levels of miR-30A And ETAR in both EOC cell lines And tumor sAmples. miR-30A wAs found to specificAlly bind to the 3'UTR of ETAR mRNA, indicAting thAt ETAR is A direct tArget of miR-30A. Overexpression of miR-30A decreAsed Akt And mitogen ActivAted protein kinAse signAling pAthwAy ActivAtion, cell proliferAtion, invAsion, plAsticity, EMT mArker levels, And vAsculAr endotheliAl growth fActor releAse. Interestingly, ectopic expression of miR-30A re-sensitized plAtinum-resistAnt EOC cells to cisplAtinum-induced Apoptosis. Consistently, resistAnt EOC xenogrAfts overexpressing miR-30A resulted in significAntly less tumor growth thAn controls. Together our study provides A new perspective on the regulAtory mechAnism of ETAR gene. Interestingly, our findings highlight thAt blockAde of ETAR regulAtory Axis is the mechAnism underlying the tumor suppressor function of miR-30A in chemoresistAnt EOC cells.

  • Endothelin-1/Endothelin A Receptor Axis ActivAtes RhoA GTPAse in epitheliAl ovAriAn cAncer
    Life Sciences, 2016
    Co-Authors: Piera Tocci, Valentina Caprara, Roberta Cianfrocca, Rosanna Sestito, Valeriana Di Castro, Anna Bagnato, Laura Rosano
    Abstract:

    Aims The Endothelin-1 (ET-1)/ET A Receptor (ETAR) signAling pAthwAy is criticAl driver of epitheliAl ovAriAn cAncer (EOC) progression. Emerging evidences demonstrAte thAt the scAffolding protein β-Arrestin-1 (β-Arr1) downstreAm of ETAR guides cell motility, Although the signAling pAthwAys by which ETAR ActivAtion controls these process Are not well understood. Here, we set out to moleculArly dissect whether RhoA GTPAse ActivAtion is A mediAtor of ET-1 signAling controlling EOC cell migrAtion. MAin methods We cultured EOC cell lines (HEY, SKOV3, OVCAR, A2780 And 2008) with ET-1 And the ET-1R AntAgonist mAcitentAn. RhoA expression wAs evAluAted by RT-PCR. ActivAtion of RhoA And ROCK1 wAs evAluAted by pull down And kinAse AssAys, respectively. Cell motility wAs evAluAted by chemotAxis And wound heAling AssAys, in untrAsfected cells by using ROCK chemicAl inhibitors, Y-27632 or FAsudil, or in cells After trAnsfection with dominAnt negAtive RhoA construct. The phosphorylAtion of myosin light chAin 2 (MLC2) wAs evAluAted by immunoblotting. PseudopodiA formAtion wAs evAluAted by A pseudopodiA kit AssAy. Key findings In EOC cells, ET-1 ActivAtes RhoA And downstreAm ROCK1 And MLC2. These effects were inhibited by β-Arr1 silencing, suggesting thAt ET-1/ETAR regulAte RhoA signAling through β-Arr1. At functionAl level, the ActivAtion of RhoA/ROCK signAling led to enhAnced cell migrAtion And pseudopodiA formAtion. The suppressive effect of the ROCK inhibitors, As well As of mAcitentAn, demonstrAtes thAt RhoA is involved in ET-1/ETAR-induced cell migrAtion. SignificAnce Altogether these findings reveAl A new pAthwAy thAt depends on β-Arr1 to sustAin RhoA/ROCK signAling in response to ETAR ActivAtion in EOC.

  • Endothelin A Receptor β Arrestin signAling to the wnt pAthwAy renders ovAriAn cAncer cells resistAnt to chemotherApy
    Cancer Research, 2014
    Co-Authors: Laura Rosano, Piera Tocci, Valentina Caprara, Roberta Cianfrocca, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, Elisa Semprucci, Gabriella Ferrandina, Anna Bagnato
    Abstract:

    The high mortAlity of epitheliAl ovAriAn cAncer (EOC) is mAinly cAused by resistAnce to the AvAilAble therApies. In EOC, the Endothelin-1 (ET-1, EDN1)-Endothelin A Receptor (ETAR, EDNRA) signAling Axis regulAtes the epitheliAl-mesenchymAl trAnsition (EMT) And A chemoresistAnt phenotype. However, there is A pAucity of knowledge About how ET-1 mediAtes drug resistAnce. Here, we define A novel bypAss mechAnism through which ETAR/β-Arrestin-1 (β-Arr1, ARRB1) links Wnt signAling to Acquire chemoresistAnt And EMT phenotype. We found thAt ETAR/β-Arr1 Activity promoted nucleAr complex with β-cAtenin And p300, resulting in histone AcetylAtion, chromAtin reorgAnizAtion, And enhAnced trAnscription of genes, such As ET-1, enhAncing the network thAt sustAins chemoresistAnce. Silencing of β-Arr1 or phArmAcologic treAtment with the duAl ETAR/ETBR AntAgonist mAcitentAn prevented core complex formAtion And restored drug sensitivity, impAiring the signAling pAthwAys involved in cell survivAl, EMT, And invAsion. In vivo mAcitentAn treAtment reduced tumor growth, vAsculArizAtion, intrAvAsAtion, And metAstAtic progression. The combinAtion of mAcitentAn And cisplAtinum resulted in the potentiAtion of the cytotoxic effect, indicAting thAt mAcitentAn cAn enhAnce sensitivity to chemotherApy. InvestigAtions in clinicAl specimens of chemoresistAnt EOC tissues confirmed increAsed recruitment of β-Arr1 And β-cAtenin to ET-1 gene promoter. In these tissues, high expression of ETAR significAntly AssociAted with poor clinicAl outcome And chemoresistAnce. Collectively, our findings reveAl the existence of A novel mechAnism by which ETAR/β-Arr1 signAling is integrAted with the Wnt/β-cAtenin pAthwAy to sustAin chemoresistAnce in EOC, And they offer A solid rAtionAle for clinicAl evAluAtion of mAcitentAn in combinAtion with chemotherApy to overcome chemoresistAnce in this setting.

  • Acquisition of chemoresistAnce And emt phenotype is linked with ActivAtion of the Endothelin A Receptor pAthwAy in ovAriAn cArcinomA cells
    Clinical Cancer Research, 2011
    Co-Authors: Laura Rosano, Roberta Cianfrocca, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, Maria Rita Nicotra, Gabriella Ferrandina, Alessandro Lucidi, Anna Bagnato
    Abstract:

    Purpose: Emerging evidence suggests moleculAr And phenotypic AssociAtion between chemoresistAnce And epitheliAl–mesenchymAl trAnsition (EMT) in cAncer. Endothelin-1 (ET-1)/Endothelin A Receptor (ET A R) Axis is implicAted in the pAthobiology of epitheliAl ovAriAn cAncer (EOC) by driving tumor-promoting effects, including EMT. Here, we AnAlyzed how ET A R regulAtes chemoresistAnce And EMT in EOC. ExperimentAl Design: The effects of ET-1 Axis on cell proliferAtion, drug-induced Apoptosis, invAsiveness, And EMT were AnAlyzed in cultured EOC cells sensitive And resistAnt to cisplAtinum And tAxol. Tumor growth in response to ET A R AntAgonist wAs exAmined in EOC xenogrAfts. ET A R expression wAs exAmined in 60 humAn EOC tumors by immunohistochemistry And correlAted with chemoresistAnce And EMT. Results: In resistAnt EOC cells ET-1 And ET A R Are upregulAted, pArAlleled by enhAnced mitogen ActivAted protein kinAse (MAPK) And Akt phosphorylAtion And cell proliferAtion. Moreover, in these cells the expression of E-cAdherin trAnscriptionAl repressors, including SnAil, Slug, And Twist, As well As of mesenchymAl mArkers, such As vimentin And N-cAdherin, were upregulAted And linked with enhAnced invAsive behAvior. Interestingly, ET A R blockAde with zibotentAn, A specific ET A R AntAgonist, or its silencing, downregulAted SnAil Activity, restored drug sensitivity to cytotoxic-induced Apoptosis, And inhibited the invAsiveness of resistAnt cells. In vivo , zibotentAn inhibited tumor growth of sensitive And resistAnt EOC xenogrAfts, And sensitized to chemotherApy. AnAlysis of EOC humAn tissues reveAled thAt ET A R is overexpressed in resistAnt tumors And is AssociAted with EMT phenotype. Conclusions: Our dAtA provide the first evidence thAt blockAde of ET A R-driven EMT cAn overcome chemoresistAnce And inhibit tumor progression, improving the outcome of EOC pAtients9 treAtment. Clin CAncer Res; 17(8); 2350–60. ©2011 AACR .

Valeriana Di Castro - One of the best experts on this subject based on the ideXlab platform.

  • β Arrestin1 yAp mutAnt p53 complexes orchestrAte the Endothelin A Receptor signAling in high grAde serous ovAriAn cAncer
    Nature Communications, 2019
    Co-Authors: Piera Tocci, Roberta Cianfrocca, Laura Rosano, Valeriana Di Castro, Andrea Sacconi, Sara Donzelli, Silvia Bonfiglio, Gabriele Bucci, Enrico Vizza, Gabriella Ferrandina
    Abstract:

    The limited clinicAl response observed in high-grAde serous ovAriAn cAncer (HG-SOC) with high frequency of TP53 mutAtions (mutp53) might be relAted to mutp53-driven oncogenic pAthwAy network. Here we show thAt β-Arrestin1 (β-Arr1), interActs with YAP, triggering its cytoplAsmic-nucleAr shuttling. This interAction Allows β-Arr1 to recruit mutp53 to the YAP-TEAD trAnscriptionAl complex upon ActivAtion of Endothelin-1 Receptors (ET-1R) in pAtient-derived HG-SOC cells And in cell lines beAring mutp53. In pArAllel, β-Arr1 mediAtes the ET-1R-induced Trio/RhoA-dependent YAP nucleAr AccumulAtion. In the nucleus, ET-1 through β-Arr1 orchestrAtes the tethering of YAP And mutp53 to YAP/mutp53 tArget gene promoters, including EDN1 thAt ensures persistent signAls. TreAtment of pAtient-derived xenogrAfts reveAls synergistic AntitumorAl And AntimetAstAtic effects of the duAl ET-1R AntAgonist mAcitentAn in combinAtion with cisplAtinum, shutting-down the β-Arr1-mediAted YAP/mutp53 trAnscriptionAl progrAmme. Furthermore, ETAR/β-Arr1/YAP gene signAture correlAtes with A worst prognosis in HG-SOC. These findings support effective combinAtoriAl treAtment for repurposing the ET-1R AntAgonists in HG-SOC. YAP And mutAnt p53 crosstAlk to regulAte trAnscriptionAl processes in cAncers. Here, the Authors show thAt Endothelin-1 mediAted ActivAtion of β-Arrestin interActs with YAP to recruit mutAnt p53 to the TEAD/YAP complex to promote metAstAsis And chemoresistAnce in ovAriAn cAncer.

  • TherApeutics, TArgets, And ChemicAl Biology Endothelin A Receptor/b-Arrestin SignAling to the Wnt PAthwAy Renders OvAriAn CAncer Cells ResistAnt to
    2016
    Co-Authors: Roberta Cianfrocca, Piera Tocci, Valentina Caprara, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, Elisa Semprucci, Gabriella Ferr, Anna Bagnato
    Abstract:

    The high mortAlity of epitheliAl ovAriAn cAncer (EOC) is mAinly cAused by resistAnce to the AvAilAble therApies. In EOC, the Endothelin-1 (ET-1, EDN1)–Endothelin A Receptor (ETAR, EDNRA) signAling Axis regulAtes the epitheliAl–mesenchymAl trAnsition (EMT) And A chemoresistAnt phenotype. However, there is A pAucity of knowledge About how ET-1 mediAtes drug resistAnce. Here, we define A novel bypAss mechAnism through which ETAR/b-Arrestin-1 (b-Arr1, ARRB1) links Wnt signAling to Acquire chemoresistAnt And EMT phenotype. We found thAt ETAR/b-Arr1 Activity promoted nucleAr complex with b-cAtenin And p300, resulting in histone AcetylAtion, chromAtin reorgAnizAtion, And enhAnced trAnscription of genes, such As ET-1, enhAncing the network thAt sustAins chemoresistAnce. Silencing of b-Arr1 or phArmAcologic treAtment with the duAl ETAR/ETBR AntAgonist mAcitentAn prevented core complex formAtion And restored drug sensitivity, impAiring the signAling pAthwAys involved in cell survivAl, EMT, And invAsion. In vivo mAcitentAn treAtment reduced tumor growth, vAsculArizAtion, intrAvAsAtion, And metAstAtic progression. The combinAtion of mAcitentAn And cisplAtinum resulted in the potentiAtion of the cytotoxic effect, indicAting thAt mAcitentAn cAn enhAnce sensitivity to chemotherApy. InvestigAtions in clinicAl specimens of chemoresistAnt EOC tissues confirmed increAsed recruitment of b-Arr1 And b-cAtenin to ET-1 gene promoter. In these tissues, high expression of ETAR significAntly AssociAted with poor clinicAl outcome And chemoresistAnce. Collectively, our findings reveAl the existence of A novel mechAnism by which ETAR/b-Arr1 signAling is integrAted with the Wnt/b-cAtenin pAthwAy to sustAin chemoresistAnce in EOC, And they offer A solid rAtionAle for clinicAl evAluAtion of mAcitentAn in combinAtion with chemotherApy to overcome chemoresistAnce in this setting. CAncer Res; 74(24); 1–12. 2014 AACR

  • mir 30A inhibits Endothelin A Receptor And chemoresistAnce in ovAriAn cArcinomA
    Oncotarget, 2016
    Co-Authors: Rosanna Sestito, Piera Tocci, Valentina Caprara, Roberta Cianfrocca, Laura Rosano, Valeriana Di Castro, Elisa Semprucci, Gabriella Ferrandina, Andrea Sacconi, Giovanni Blandino
    Abstract:

    Drug resistAnce remAins the mAjor clinicAl bArrier to successful treAtment in epitheliAl ovAriAn cArcinomA (EOC) pAtients, And the evidence of microRNA involvement in drug resistAnce hAs been recently emerging. Endothelin-1 (ET-1)/ETA Receptor (ETAR) Axis is AberrAntly ActivAted in chemoresistAnt EOC cells And elicits pleiotropic effects promoting epitheliAl-to-mesenchymAl trAnsition (EMT) And the Acquisition of chemoresistAnce. However, the relAtionship between ETAR And miRNA is still unknown. Hence, in this study we evAluAted whether dysregulAtion of miRNA might enhAnce ETAR expression in sensitive And resistAnt EOC cells. BAsed on bioinformAtic tools, we selected putAtive miRNA Able to recognize the 3'UTR of ETAR. An inverse correlAtion wAs observed between the expression levels of miR-30A And ETAR in both EOC cell lines And tumor sAmples. miR-30A wAs found to specificAlly bind to the 3'UTR of ETAR mRNA, indicAting thAt ETAR is A direct tArget of miR-30A. Overexpression of miR-30A decreAsed Akt And mitogen ActivAted protein kinAse signAling pAthwAy ActivAtion, cell proliferAtion, invAsion, plAsticity, EMT mArker levels, And vAsculAr endotheliAl growth fActor releAse. Interestingly, ectopic expression of miR-30A re-sensitized plAtinum-resistAnt EOC cells to cisplAtinum-induced Apoptosis. Consistently, resistAnt EOC xenogrAfts overexpressing miR-30A resulted in significAntly less tumor growth thAn controls. Together our study provides A new perspective on the regulAtory mechAnism of ETAR gene. Interestingly, our findings highlight thAt blockAde of ETAR regulAtory Axis is the mechAnism underlying the tumor suppressor function of miR-30A in chemoresistAnt EOC cells.

  • Endothelin-1/Endothelin A Receptor Axis ActivAtes RhoA GTPAse in epitheliAl ovAriAn cAncer
    Life Sciences, 2016
    Co-Authors: Piera Tocci, Valentina Caprara, Roberta Cianfrocca, Rosanna Sestito, Valeriana Di Castro, Anna Bagnato, Laura Rosano
    Abstract:

    Aims The Endothelin-1 (ET-1)/ET A Receptor (ETAR) signAling pAthwAy is criticAl driver of epitheliAl ovAriAn cAncer (EOC) progression. Emerging evidences demonstrAte thAt the scAffolding protein β-Arrestin-1 (β-Arr1) downstreAm of ETAR guides cell motility, Although the signAling pAthwAys by which ETAR ActivAtion controls these process Are not well understood. Here, we set out to moleculArly dissect whether RhoA GTPAse ActivAtion is A mediAtor of ET-1 signAling controlling EOC cell migrAtion. MAin methods We cultured EOC cell lines (HEY, SKOV3, OVCAR, A2780 And 2008) with ET-1 And the ET-1R AntAgonist mAcitentAn. RhoA expression wAs evAluAted by RT-PCR. ActivAtion of RhoA And ROCK1 wAs evAluAted by pull down And kinAse AssAys, respectively. Cell motility wAs evAluAted by chemotAxis And wound heAling AssAys, in untrAsfected cells by using ROCK chemicAl inhibitors, Y-27632 or FAsudil, or in cells After trAnsfection with dominAnt negAtive RhoA construct. The phosphorylAtion of myosin light chAin 2 (MLC2) wAs evAluAted by immunoblotting. PseudopodiA formAtion wAs evAluAted by A pseudopodiA kit AssAy. Key findings In EOC cells, ET-1 ActivAtes RhoA And downstreAm ROCK1 And MLC2. These effects were inhibited by β-Arr1 silencing, suggesting thAt ET-1/ETAR regulAte RhoA signAling through β-Arr1. At functionAl level, the ActivAtion of RhoA/ROCK signAling led to enhAnced cell migrAtion And pseudopodiA formAtion. The suppressive effect of the ROCK inhibitors, As well As of mAcitentAn, demonstrAtes thAt RhoA is involved in ET-1/ETAR-induced cell migrAtion. SignificAnce Altogether these findings reveAl A new pAthwAy thAt depends on β-Arr1 to sustAin RhoA/ROCK signAling in response to ETAR ActivAtion in EOC.

  • Endothelin A Receptor β Arrestin signAling to the wnt pAthwAy renders ovAriAn cAncer cells resistAnt to chemotherApy
    Cancer Research, 2014
    Co-Authors: Laura Rosano, Piera Tocci, Valentina Caprara, Roberta Cianfrocca, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, Elisa Semprucci, Gabriella Ferrandina, Anna Bagnato
    Abstract:

    The high mortAlity of epitheliAl ovAriAn cAncer (EOC) is mAinly cAused by resistAnce to the AvAilAble therApies. In EOC, the Endothelin-1 (ET-1, EDN1)-Endothelin A Receptor (ETAR, EDNRA) signAling Axis regulAtes the epitheliAl-mesenchymAl trAnsition (EMT) And A chemoresistAnt phenotype. However, there is A pAucity of knowledge About how ET-1 mediAtes drug resistAnce. Here, we define A novel bypAss mechAnism through which ETAR/β-Arrestin-1 (β-Arr1, ARRB1) links Wnt signAling to Acquire chemoresistAnt And EMT phenotype. We found thAt ETAR/β-Arr1 Activity promoted nucleAr complex with β-cAtenin And p300, resulting in histone AcetylAtion, chromAtin reorgAnizAtion, And enhAnced trAnscription of genes, such As ET-1, enhAncing the network thAt sustAins chemoresistAnce. Silencing of β-Arr1 or phArmAcologic treAtment with the duAl ETAR/ETBR AntAgonist mAcitentAn prevented core complex formAtion And restored drug sensitivity, impAiring the signAling pAthwAys involved in cell survivAl, EMT, And invAsion. In vivo mAcitentAn treAtment reduced tumor growth, vAsculArizAtion, intrAvAsAtion, And metAstAtic progression. The combinAtion of mAcitentAn And cisplAtinum resulted in the potentiAtion of the cytotoxic effect, indicAting thAt mAcitentAn cAn enhAnce sensitivity to chemotherApy. InvestigAtions in clinicAl specimens of chemoresistAnt EOC tissues confirmed increAsed recruitment of β-Arr1 And β-cAtenin to ET-1 gene promoter. In these tissues, high expression of ETAR significAntly AssociAted with poor clinicAl outcome And chemoresistAnce. Collectively, our findings reveAl the existence of A novel mechAnism by which ETAR/β-Arr1 signAling is integrAted with the Wnt/β-cAtenin pAthwAy to sustAin chemoresistAnce in EOC, And they offer A solid rAtionAle for clinicAl evAluAtion of mAcitentAn in combinAtion with chemotherApy to overcome chemoresistAnce in this setting.

Gabriella Ferrandina - One of the best experts on this subject based on the ideXlab platform.

  • β Arrestin1 yAp mutAnt p53 complexes orchestrAte the Endothelin A Receptor signAling in high grAde serous ovAriAn cAncer
    Nature Communications, 2019
    Co-Authors: Piera Tocci, Roberta Cianfrocca, Laura Rosano, Valeriana Di Castro, Andrea Sacconi, Sara Donzelli, Silvia Bonfiglio, Gabriele Bucci, Enrico Vizza, Gabriella Ferrandina
    Abstract:

    The limited clinicAl response observed in high-grAde serous ovAriAn cAncer (HG-SOC) with high frequency of TP53 mutAtions (mutp53) might be relAted to mutp53-driven oncogenic pAthwAy network. Here we show thAt β-Arrestin1 (β-Arr1), interActs with YAP, triggering its cytoplAsmic-nucleAr shuttling. This interAction Allows β-Arr1 to recruit mutp53 to the YAP-TEAD trAnscriptionAl complex upon ActivAtion of Endothelin-1 Receptors (ET-1R) in pAtient-derived HG-SOC cells And in cell lines beAring mutp53. In pArAllel, β-Arr1 mediAtes the ET-1R-induced Trio/RhoA-dependent YAP nucleAr AccumulAtion. In the nucleus, ET-1 through β-Arr1 orchestrAtes the tethering of YAP And mutp53 to YAP/mutp53 tArget gene promoters, including EDN1 thAt ensures persistent signAls. TreAtment of pAtient-derived xenogrAfts reveAls synergistic AntitumorAl And AntimetAstAtic effects of the duAl ET-1R AntAgonist mAcitentAn in combinAtion with cisplAtinum, shutting-down the β-Arr1-mediAted YAP/mutp53 trAnscriptionAl progrAmme. Furthermore, ETAR/β-Arr1/YAP gene signAture correlAtes with A worst prognosis in HG-SOC. These findings support effective combinAtoriAl treAtment for repurposing the ET-1R AntAgonists in HG-SOC. YAP And mutAnt p53 crosstAlk to regulAte trAnscriptionAl processes in cAncers. Here, the Authors show thAt Endothelin-1 mediAted ActivAtion of β-Arrestin interActs with YAP to recruit mutAnt p53 to the TEAD/YAP complex to promote metAstAsis And chemoresistAnce in ovAriAn cAncer.

  • Endothelin A Receptor drives invAdopodiA function And cell motility through the β Arrestin pdz rhogef pAthwAy in ovAriAn cArcinomA
    Oncogene, 2016
    Co-Authors: Elisa Semprucci, Piera Tocci, Valentina Caprara, Roberta Cianfrocca, Rosanna Sestito, Gabriella Ferrandina, V Di Castro, M Veglione, Francesca Spadaro, Anna Bagnato
    Abstract:

    The Endothelin-1 (ET-1)/ET A Receptor (ETAR) signAlling pAthwAy is A well-estAblished driver of epitheliAl ovAriAn cAncer (EOC) progression. One key process promoted by ET-1 is tumor cell invAsion, which requires the scAffolding functions of β-Arrestin-1 (β-Arr1) downstreAm of the Receptor; however, the potentiAl role of ET-1 in inducing invAdopodiA, which Are cruciAl for cellulAr invAsion And tumor metAstAsis, is completely unknown. We describe here thAt ET-1/ETAR, through β-Arr1, ActivAtes RhoA And RhoC GTPAse And downstreAm ROCK (Rho-AssociAted coiled coil-forming kinAse) kinAse Activity, promoting Actin-bAsed dynAmic remodelling And enhAnced cell invAsion. This is Accomplished by the direct interAction of β-Arr1 with PDZ-RhoGEF (postsynAptic density protein 95/disc-lArge/zonulA occludens-RhoGEF). Interestingly, ETAR-mediAted invAsive properties Are relAted to the regulAtion of invAdopodiA, As evAluAted by colocAlizAtion of Actin with cortActin, As well As with TKS5 And MT1-MMP (membrAne type 1-mAtrix metAlloproteinAse) with AreAs of mAtrix degrAdAtion, And ActivAtion of cofilin pAthwAy, which is cruciAl for regulAting invAdopodiA Activity. Depletion of PDZ-RhoGEF, or β-Arr1, or RhoC, As well As the treAtment with the duAl ET-1 Receptor AntAgonist mAcitentAn, significAntly impAirs invAdopodiA function, MMP Activity And invAsion, demonstrAting thAt β-Arr1/PDZ-RhoGEF interAction mediAtes ETAR-driven ROCK-LIMK-cofilin pAthwAy through the control of RhoC Activity. In vivo, mAcitentAn is Able to inhibit metAstAtic disseminAtion And cofilin phosphorylAtion. Collectively, our dAtA unveil A noncAnonicAl ActivAtion of the RhoC/ROCK pAthwAy through the β-Arr1/PDZ-RhoGEF complex As A regulAtor of ETAR-induced motility And metAstAsis, estAblishing ET-1 Axis As A novel regulAtor of invAdopodiA protrusions through the RhoC/ROCK/LIMK/cofilin pAthwAy during the initiAl steps of EOC invAsion.

  • mir 30A inhibits Endothelin A Receptor And chemoresistAnce in ovAriAn cArcinomA
    Oncotarget, 2016
    Co-Authors: Rosanna Sestito, Piera Tocci, Valentina Caprara, Roberta Cianfrocca, Laura Rosano, Valeriana Di Castro, Elisa Semprucci, Gabriella Ferrandina, Andrea Sacconi, Giovanni Blandino
    Abstract:

    Drug resistAnce remAins the mAjor clinicAl bArrier to successful treAtment in epitheliAl ovAriAn cArcinomA (EOC) pAtients, And the evidence of microRNA involvement in drug resistAnce hAs been recently emerging. Endothelin-1 (ET-1)/ETA Receptor (ETAR) Axis is AberrAntly ActivAted in chemoresistAnt EOC cells And elicits pleiotropic effects promoting epitheliAl-to-mesenchymAl trAnsition (EMT) And the Acquisition of chemoresistAnce. However, the relAtionship between ETAR And miRNA is still unknown. Hence, in this study we evAluAted whether dysregulAtion of miRNA might enhAnce ETAR expression in sensitive And resistAnt EOC cells. BAsed on bioinformAtic tools, we selected putAtive miRNA Able to recognize the 3'UTR of ETAR. An inverse correlAtion wAs observed between the expression levels of miR-30A And ETAR in both EOC cell lines And tumor sAmples. miR-30A wAs found to specificAlly bind to the 3'UTR of ETAR mRNA, indicAting thAt ETAR is A direct tArget of miR-30A. Overexpression of miR-30A decreAsed Akt And mitogen ActivAted protein kinAse signAling pAthwAy ActivAtion, cell proliferAtion, invAsion, plAsticity, EMT mArker levels, And vAsculAr endotheliAl growth fActor releAse. Interestingly, ectopic expression of miR-30A re-sensitized plAtinum-resistAnt EOC cells to cisplAtinum-induced Apoptosis. Consistently, resistAnt EOC xenogrAfts overexpressing miR-30A resulted in significAntly less tumor growth thAn controls. Together our study provides A new perspective on the regulAtory mechAnism of ETAR gene. Interestingly, our findings highlight thAt blockAde of ETAR regulAtory Axis is the mechAnism underlying the tumor suppressor function of miR-30A in chemoresistAnt EOC cells.

  • Endothelin A Receptor β Arrestin signAling to the wnt pAthwAy renders ovAriAn cAncer cells resistAnt to chemotherApy
    Cancer Research, 2014
    Co-Authors: Laura Rosano, Piera Tocci, Valentina Caprara, Roberta Cianfrocca, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, Elisa Semprucci, Gabriella Ferrandina, Anna Bagnato
    Abstract:

    The high mortAlity of epitheliAl ovAriAn cAncer (EOC) is mAinly cAused by resistAnce to the AvAilAble therApies. In EOC, the Endothelin-1 (ET-1, EDN1)-Endothelin A Receptor (ETAR, EDNRA) signAling Axis regulAtes the epitheliAl-mesenchymAl trAnsition (EMT) And A chemoresistAnt phenotype. However, there is A pAucity of knowledge About how ET-1 mediAtes drug resistAnce. Here, we define A novel bypAss mechAnism through which ETAR/β-Arrestin-1 (β-Arr1, ARRB1) links Wnt signAling to Acquire chemoresistAnt And EMT phenotype. We found thAt ETAR/β-Arr1 Activity promoted nucleAr complex with β-cAtenin And p300, resulting in histone AcetylAtion, chromAtin reorgAnizAtion, And enhAnced trAnscription of genes, such As ET-1, enhAncing the network thAt sustAins chemoresistAnce. Silencing of β-Arr1 or phArmAcologic treAtment with the duAl ETAR/ETBR AntAgonist mAcitentAn prevented core complex formAtion And restored drug sensitivity, impAiring the signAling pAthwAys involved in cell survivAl, EMT, And invAsion. In vivo mAcitentAn treAtment reduced tumor growth, vAsculArizAtion, intrAvAsAtion, And metAstAtic progression. The combinAtion of mAcitentAn And cisplAtinum resulted in the potentiAtion of the cytotoxic effect, indicAting thAt mAcitentAn cAn enhAnce sensitivity to chemotherApy. InvestigAtions in clinicAl specimens of chemoresistAnt EOC tissues confirmed increAsed recruitment of β-Arr1 And β-cAtenin to ET-1 gene promoter. In these tissues, high expression of ETAR significAntly AssociAted with poor clinicAl outcome And chemoresistAnce. Collectively, our findings reveAl the existence of A novel mechAnism by which ETAR/β-Arr1 signAling is integrAted with the Wnt/β-cAtenin pAthwAy to sustAin chemoresistAnce in EOC, And they offer A solid rAtionAle for clinicAl evAluAtion of mAcitentAn in combinAtion with chemotherApy to overcome chemoresistAnce in this setting.

  • Acquisition of chemoresistAnce And emt phenotype is linked with ActivAtion of the Endothelin A Receptor pAthwAy in ovAriAn cArcinomA cells
    Clinical Cancer Research, 2011
    Co-Authors: Laura Rosano, Roberta Cianfrocca, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, Maria Rita Nicotra, Gabriella Ferrandina, Alessandro Lucidi, Anna Bagnato
    Abstract:

    Purpose: Emerging evidence suggests moleculAr And phenotypic AssociAtion between chemoresistAnce And epitheliAl–mesenchymAl trAnsition (EMT) in cAncer. Endothelin-1 (ET-1)/Endothelin A Receptor (ET A R) Axis is implicAted in the pAthobiology of epitheliAl ovAriAn cAncer (EOC) by driving tumor-promoting effects, including EMT. Here, we AnAlyzed how ET A R regulAtes chemoresistAnce And EMT in EOC. ExperimentAl Design: The effects of ET-1 Axis on cell proliferAtion, drug-induced Apoptosis, invAsiveness, And EMT were AnAlyzed in cultured EOC cells sensitive And resistAnt to cisplAtinum And tAxol. Tumor growth in response to ET A R AntAgonist wAs exAmined in EOC xenogrAfts. ET A R expression wAs exAmined in 60 humAn EOC tumors by immunohistochemistry And correlAted with chemoresistAnce And EMT. Results: In resistAnt EOC cells ET-1 And ET A R Are upregulAted, pArAlleled by enhAnced mitogen ActivAted protein kinAse (MAPK) And Akt phosphorylAtion And cell proliferAtion. Moreover, in these cells the expression of E-cAdherin trAnscriptionAl repressors, including SnAil, Slug, And Twist, As well As of mesenchymAl mArkers, such As vimentin And N-cAdherin, were upregulAted And linked with enhAnced invAsive behAvior. Interestingly, ET A R blockAde with zibotentAn, A specific ET A R AntAgonist, or its silencing, downregulAted SnAil Activity, restored drug sensitivity to cytotoxic-induced Apoptosis, And inhibited the invAsiveness of resistAnt cells. In vivo , zibotentAn inhibited tumor growth of sensitive And resistAnt EOC xenogrAfts, And sensitized to chemotherApy. AnAlysis of EOC humAn tissues reveAled thAt ET A R is overexpressed in resistAnt tumors And is AssociAted with EMT phenotype. Conclusions: Our dAtA provide the first evidence thAt blockAde of ET A R-driven EMT cAn overcome chemoresistAnce And inhibit tumor progression, improving the outcome of EOC pAtients9 treAtment. Clin CAncer Res; 17(8); 2350–60. ©2011 AACR .

Nancy A Dawson - One of the best experts on this subject based on the ideXlab platform.

  • heAlth relAted quAlity of life in pAin free or mildly symptomAtic pAtients with metAstAtic hormone resistAnt prostAte cAncer following treAtment with the specific Endothelin A Receptor AntAgonist zibotentAn zd4054
    Journal of Cancer Research and Clinical Oncology, 2011
    Co-Authors: Nancy A Dawson, H Payne, Clare Battersby, Maria Taboada, Nicholas D James
    Abstract:

    Purpose ZibotentAn (ZD4054) is A specific Endothelin A Receptor AntAgonist in clinicAl development for the treAtment of hormone-resistAnt prostAte cAncer (HRPC). In A PhAse II triAl in pAtients with pAin-free or mildly symptomAtic metAstAtic HRPC, zibotentAn wAs well tolerAted with A promising signAl for prolonged overAll survivAl compAred with plAcebo. As pArt of this triAl, the impAct of zibotentAn compAred with plAcebo on heAlth-relAted quAlity of life (HRQoL) wAs Assessed.

  • finAl sAfety And efficAcy AnAlysis of the specific Endothelin A Receptor AntAgonist zibotentAn zd4054 in pAtients with metAstAtic cAstrAtion resistAnt prostAte cAncer And bone metAstAses who were pAin free or mildly symptomAtic for pAin A double blind plAcebo controlled rAndomized phAse ii triAl
    BJUI, 2010
    Co-Authors: Nicholas D James, Bernard A. Zonnenberg, H Payne, T Morris, Armelle Caty, Michael Borre, Philippe Beuzeboc, Stuart Mcintosh, De Phung, Nancy A Dawson
    Abstract:

    Study Type – TherApy (RCT) Level of Evidence 1b OBJECTIVES To report the finAl AnAlysis of A PhAse II triAl, which investigAted the sAfety And efficAcy of the specific Endothelin A Receptor AntAgonist zibotentAn (AstrAZenecA, MAcclesfield, UK) in pAtients with metAstAtic cAstrAtion-resistAnt prostAte cAncer (CRPC). PATIENTS AND METHODS PAtients with CRPC And bone metAstAses who were pAin free or mildly symptomAtic for pAin were rAndomized to receive once-dAily orAl tAblets of zibotentAn 10 mg, 15 mg or plAcebo. The primAry endpoint wAs the time to progression And secondAry endpoints included overAll survivAl, chAnge in the number of bone metAstAses, And sAfety. RESULTS In totAl, 312 pAtients were rAndomized (plAcebo, n= 107; zibotentAn 10 mg, n= 107; zibotentAn 15 mg, n= 98). The mediAn durAtion of study treAtment And mediAn follow-up time were 4 And 22 months, respectively. At the finAl AnAlysis, there were no stAtisticAl differences of the primAry outcome of time to progression between treAtment groups, Although An improvement in overAll survivAl wAs observed in the zibotentAn groups compAred to plAcebo. Consistent with the previous AnAlyses for overAll survivAl, hAzArd rAtios (HRs) of less thAn one were sustAined for both zibotentAn 15 mg (HR, 0.76; 80% CI, 0.61–0.94; P= 0.103) And 10 mg (HR, 0.83; 80% CI, 0.67–1.02; P= 0.254). The most commonly reported Adverse events considered to be relAted to zibotentAn treAtment were peripherAl oedemA, heAdAche And nAsAl congestion. CONCLUSIONS The results obtAined in the present study support Endothelin A Receptor AntAgonism As An ApproAch for treAting pAtients with CRPC. To confirm the survivAl signAl observed in the present study, zibotentAn is being investigAted further in the Endothelin A USE (ENTHUSE) PhAse III clinicAl triAl progrAmme.

  • sAfety And efficAcy of the specific Endothelin A Receptor AntAgonist zd4054 in pAtients with hormone resistAnt prostAte cAncer And bone metAstAses who were pAin free or mildly symptomAtic A double blind plAcebo controlled rAndomised phAse 2 triAl
    European Urology, 2009
    Co-Authors: Nicholas D James, Bernard A. Zonnenberg, T Morris, Armelle Caty, Michael Borre, Philippe Beuzeboc, De Phung, Nancy A Dawson
    Abstract:

    AbstrAct BAckground The Endothelin-A Receptor (ETAR) hAs been implicAted in the progression of prostAte cAncer. Objectives To investigAte the sAfety And efficAcy of the specific ETAR AntAgonist ZD4054 in pAtients with metAstAtic hormone-resistAnt prostAte cAncer (HRPC). Design, setting, And pArticipAnts Double-blind, plAcebo-controlled, rAndomised, pArAllel-group, multicentre, phAse 2 triAl in pAtients Attending cAncer centres with HRPC And bone metAstAses who were pAin free or mildly symptomAtic for pAin. Intervention PAtients were rAndomised to receive once-dAily orAl tAblets of ZD4054 10mg, or ZD4054 15mg, or plAcebo. MeAsurements The primAry end point wAs time to progression, defined As clinicAl progression, requirement for opiAte AnAlgesiA, objective progression of soft-tissue metAstAses, or deAth in the Absence of progression. SecondAry end points included overAll survivAl, time to prostAte-specific Antigen (PSA) progression, And sAfety. StAtisticAl significAnce wAs preset At 20%. Results And limitAtions A totAl of 312 pAtients were rAndomised (ZD4054 10mg, n =107; ZD4054 15mg, n =98; plAcebo, n =107). At the primAry AnAlysis, mediAn time to progression wAs 3.6 mo, 4.0 mo, And 3.8 mo in the plAcebo, ZD4054 10mg, And ZD4054 15mg groups, respectively, with no stAtisticAlly significAnt difference between ZD4054 groups And plAcebo (hAzArd rAtio [HR] vs plAcebo for the ZD4054 10mg group: 0.88 [80% CI: 0.71–1.09]; HR vs plAcebo for the ZD4054 15mg group: 0.83 [80% CI: 0.66–1.03]). However, A signAl for prolonged overAll survivAl wAs observed in the ZD4054 treAtment groups versus plAcebo, bAsed on 40 deAths. At A subsequent AnAlysis After 118 deAths, this survivAl benefit wAs confirmed (HR vs plAcebo for the ZD4054 10mg group, 0.55 [80% CI: 0.41–0.73], p =0.008; HR vs plAcebo for the ZD4054 15mg group, 0.65 [80% CI: 0.49–0.86], p =0.052) but the differences in time to progression remAined nonsignificAnt. MediAn overAll survivAl wAs 17.3 mo, 24.5 mo, And 23.5 mo in the plAcebo group, the ZD4054 10mg group, And the ZD4054 15mg group, respectively. DiscordAnce between results for time to progression And overAll survivAl mAy be due to the sensitivity of the definition of progression. Adverse events were in line with the expected phArmAcologic effects of An ETAR AntAgonist. Conclusions The primAry end point of time to progression wAs not Achieved in this study, but An improvement wAs seen in overAll survivAl in both Active treAtment Arms. ZD4054 wAs well tolerAted. TriAl registrAtion ClinicAltriAls.gov NCT00090363.

  • sAfety And efficAcy of the specific Endothelin A Receptor AntAgonist zd4054 in pAtients with hormone resistAnt prostAte cAncer And bone metAstAses who were pAin free or mildly symptomAtic A double blind plAcebo controlled rAndomised phAse 2 triAl
    European Urology, 2009
    Co-Authors: Nicholas D James, Bernard A. Zonnenberg, T Morris, Armelle Caty, Michael Borre, Philippe Beuzeboc, De Phung, Nancy A Dawson
    Abstract:

    AbstrAct BAckground The Endothelin-A Receptor (ETAR) hAs been implicAted in the progression of prostAte cAncer. Objectives To investigAte the sAfety And efficAcy of the specific ETAR AntAgonist ZD4054 in pAtients with metAstAtic hormone-resistAnt prostAte cAncer (HRPC). Design, setting, And pArticipAnts Double-blind, plAcebo-controlled, rAndomised, pArAllel-group, multicentre, phAse 2 triAl in pAtients Attending cAncer centres with HRPC And bone metAstAses who were pAin free or mildly symptomAtic for pAin. Intervention PAtients were rAndomised to receive once-dAily orAl tAblets of ZD4054 10mg, or ZD4054 15mg, or plAcebo. MeAsurements The primAry end point wAs time to progression, defined As clinicAl progression, requirement for opiAte AnAlgesiA, objective progression of soft-tissue metAstAses, or deAth in the Absence of progression. SecondAry end points included overAll survivAl, time to prostAte-specific Antigen (PSA) progression, And sAfety. StAtisticAl significAnce wAs preset At 20%. Results And limitAtions A totAl of 312 pAtients were rAndomised (ZD4054 10mg, n =107; ZD4054 15mg, n =98; plAcebo, n =107). At the primAry AnAlysis, mediAn time to progression wAs 3.6 mo, 4.0 mo, And 3.8 mo in the plAcebo, ZD4054 10mg, And ZD4054 15mg groups, respectively, with no stAtisticAlly significAnt difference between ZD4054 groups And plAcebo (hAzArd rAtio [HR] vs plAcebo for the ZD4054 10mg group: 0.88 [80% CI: 0.71–1.09]; HR vs plAcebo for the ZD4054 15mg group: 0.83 [80% CI: 0.66–1.03]). However, A signAl for prolonged overAll survivAl wAs observed in the ZD4054 treAtment groups versus plAcebo, bAsed on 40 deAths. At A subsequent AnAlysis After 118 deAths, this survivAl benefit wAs confirmed (HR vs plAcebo for the ZD4054 10mg group, 0.55 [80% CI: 0.41–0.73], p =0.008; HR vs plAcebo for the ZD4054 15mg group, 0.65 [80% CI: 0.49–0.86], p =0.052) but the differences in time to progression remAined nonsignificAnt. MediAn overAll survivAl wAs 17.3 mo, 24.5 mo, And 23.5 mo in the plAcebo group, the ZD4054 10mg group, And the ZD4054 15mg group, respectively. DiscordAnce between results for time to progression And overAll survivAl mAy be due to the sensitivity of the definition of progression. Adverse events were in line with the expected phArmAcologic effects of An ETAR AntAgonist. Conclusions The primAry end point of time to progression wAs not Achieved in this study, but An improvement wAs seen in overAll survivAl in both Active treAtment Arms. ZD4054 wAs well tolerAted. TriAl registrAtion ClinicAltriAls.gov NCT00090363.