02972nas a2200445   4500008004100000022001400041245010400055210006900159260001600228490000700244520152100251653001901772653001301791653001101804653003201815653001501847653002901862653001901891653002401910100002601934700002201960700002801982700003002010700002802040700002702068700002702095700003002122700002802152700002202180700002002202700001602222700001902238700002802257700002202285700001602307700002402323700002402347700002202371856013302393       2022                        eng d  a1422-006700aEndoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions.0 aEndoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modu  c2022 Aug 040 v233 a<p>Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.</p>10aBone Neoplasms10aEndoglin10aHumans10aMatrix Metalloproteinase 1410aProteomics10aReceptors, Growth Factor10aSarcoma, Ewing10aSignal Transduction1 aPuerto-Camacho, Pilar1 aDiaz-Martin, Juan1 aOlmedo-Pelayo, Joaquín1 aBolado-Carrancio, Alfonso1 aSalguero-Aranda, Carmen1 aJordán-Pérez, Carmen1 aEsteban-Medina, Marina1 aAlamo-Alvarez, Inmaculada1 aDelgado-Bellido, Daniel1 aLobo-Selma, Laura1 aDopazo, Joaquin1 aSastre, Ana1 aAlonso, Javier1 aGrünewald, Thomas, G P1 aBernabeu, Carmelo1 aByron, Adam1 aBrunton, Valerie, G1 aAmaral, Ana, Teresa1 ade Alava, Enrique  uhttps://www.clinbioinfosspa.es/content/endoglin-and-mmp14-contribute-ewing-sarcoma-spreading-modulation-cell-matrix-interactions04661nas a2200625   4500008004100000022001400041245010700055210006900162260001200231300001200243490000700255520277400262653000903036653001103045653002203056653001103078653001403089653000903103653001603112653002403128653001403152653002403166653003003190653001603220653004903236653002803285653001703313653001803330100002503348700001903373700001903392700001903411700001703430700001603447700002003463700002103483700002203504700003403526700002003560700002403580700002303604700001903627700002003646700002003666700002503686700002303711700002203734700002003756700002903776700003203805700002103837700002003858700002403878856013303902       2020                        eng d  a1474-548800aPazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial.0 aPazopanib for treatment of typical solitary fibrous tumours a mu  c2020 03  a456-4660 v213 a<p><b>BACKGROUND: </b>Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.</p><p><b>METHODS: </b>In this single-arm, phase 2 trial, adult patients (aged ≥18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15.</p><p><b>FINDINGS: </b>From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58%) of 31 patients had a partial response, 12 (39%) had stable disease, and one (3%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58% (95% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53%] of 34 patients), fatigue (17 [50%]), and hypertension (17 [50%]).</p><p><b>INTERPRETATION: </b>To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour.</p><p><b>FUNDING: </b>Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.</p>10aAged10aFemale10aFollow-Up Studies10aHumans10aIndazoles10aMale10aMiddle Aged10aNeoplasm Metastasis10aPrognosis10aProspective Studies10aProtein Kinase Inhibitors10aPyrimidines10aResponse Evaluation Criteria in Solid Tumors10aSolitary Fibrous Tumors10aSulfonamides10aSurvival Rate1 aMartin-Broto, Javier1 aCruz, Josefina1 aPenel, Nicolas1 aLe Cesne, Axel1 aHindi, Nadia1 aLuna, Pablo1 aMoura, David, S1 aBernabeu, Daniel1 ade Alava, Enrique1 aLopez-Guerrero, Jose, Antonio1 aDopazo, Joaquin1 aPeña-Chilet, Maria1 aGutierrez, Antonio1 aCollini, Paola1 aKaranian, Marie1 aRedondo, Andres1 aLopez-Pousa, Antonio1 aGrignani, Giovanni1 aDiaz-Martin, Juan1 aMarcilla, David1 aFernandez-Serra, Antonio1 aGonzalez-Aguilera, Cristina1 aCasali, Paolo, G1 aBlay, Jean-Yves1 aStacchiotti, Silvia  uhttps://www.clinbioinfosspa.es/content/pazopanib-treatment-typical-solitary-fibrous-tumours-multicentre-single-arm-phase-2-trial05186nas a2200661   4500008004100000022001400041245013800055210006900193260001200262300001200274490000700286520316900293653001003462653000903472653002803481653002603509653001103535653001103546653001403557653000903571653001603580653002603596653001603622653004903638653002603687653002803713653001703741653002203758100002503780700002403805700002503829700002003854700002103874700002203895700002103917700002203938700002303960700002003983700002404003700002204027700002204049700001804071700001904089700003004108700002904138700002304167700001804190700002904208700002404237700001704261700001504278700002004293700002704313700001804340700002004358700001904378856012704397       2019                        eng d  a1474-548800aPazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.0 aPazopanib for treatment of advanced malignant and dedifferentiat  c2019 01  a134-1440 v203 a<p><b>BACKGROUND: </b>A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.</p><p><b>METHODS: </b>In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.</p><p><b>FINDINGS: </b>From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).</p><p><b>INTERPRETATION: </b>To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.</p><p><b>FUNDING: </b>Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.</p>10aAdult10aAged10aAngiogenesis Inhibitors10aAntineoplastic Agents10aFemale10aHumans10aIndazoles10aMale10aMiddle Aged10aMultivariate Analysis10aPyrimidines10aResponse Evaluation Criteria in Solid Tumors10aSoft Tissue Neoplasms10aSolitary Fibrous Tumors10aSulfonamides10aSurvival Analysis1 aMartin-Broto, Javier1 aStacchiotti, Silvia1 aLopez-Pousa, Antonio1 aRedondo, Andres1 aBernabeu, Daniel1 ade Alava, Enrique1 aCasali, Paolo, G1 aItaliano, Antoine1 aGutierrez, Antonio1 aMoura, David, S1 aPeña-Chilet, Maria1 aDiaz-Martin, Juan1 aBiscuola, Michele1 aTaron, Miguel1 aCollini, Paola1 aRanchere-Vince, Dominique1 aDel Muro, Xavier, Garcia1 aGrignani, Giovanni1 aDumont, Sarah1 aMartinez-Trufero, Javier1 aPalmerini, Emanuela1 aHindi, Nadia1 aSebio, Ana1 aDopazo, Joaquin1 aTos, Angelo, Paolo Dei1 aLeCesne, Axel1 aBlay, Jean-Yves1 aCruz, Josefina  uhttps://www.clinbioinfosspa.es/content/pazopanib-treatment-advanced-malignant-and-dedifferentiated-solitary-fibrous-tumour