{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T18:27:42Z","timestamp":1793471262922,"version":"4.5.0"},"reference-count":17,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2010,2,10]]},"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p> Perivascular epithelioid cell tumors (PEComas) represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. There is no known effective therapy for PEComa, and the molecular pathophysiology of aberrant mTOR signaling provided us with a scientific rationale to target this pathway therapeutically. On this mechanistic basis, we treated three consecutive patients with metastatic PEComa with an oral mTOR inhibitor, sirolimus. <\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p> Patients with advanced PEComa were treated with sirolimus and consented to retrospective collection of data from their medical records and analysis of archival tumor specimens. Tumor response was determined by computed tomography scans obtained at the clinical discretion of the treating physicians. Tumors were assessed for immunohistochemical evidence of mTORC1 activation and genetic evidence of alterations in TSC1 and TSC2. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p> Radiographic responses to sirolimus were observed in all patients. PEComas demonstrated loss of TSC2 protein expression and evidence of baseline mTORC1 activation. Homozygous loss of TSC1 was identified in one PEComa. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p> Inhibition of mTORC1, pathologically activated by loss of the TSC1\/TSC2 tumor suppressor complex, is a rational mechanistic target for therapy in PEComas. The clinical activity of sirolimus in PEComa additionally strengthens the pathobiologic similarities linking PEComas to other neoplasms related to the tuberous sclerosis complex. <\/jats:p><\/jats:sec>","DOI":"10.1200\/jco.2009.25.2981","type":"journal-article","created":{"date-parts":[[2010,1,5]],"date-time":"2010-01-05T02:49:38Z","timestamp":1262659778000},"page":"835-840","source":"Crossref","is-referenced-by-count":345,"title":["Clinical Activity of mTOR Inhibition With Sirolimus in Malignant Perivascular Epithelioid Cell Tumors: Targeting the Pathogenic Activation of mTORC1 in Tumors"],"prefix":"10.1200","volume":"28","author":[{"given":"Andrew J.","family":"Wagner","sequence":"first","affiliation":[{"name":"From the Center for Sarcoma and Bone Oncology and Ludwig Center for Cancer Research; and Department of Radiology, Dana-Farber Cancer Institute; Harvard Medical School; Division of Translational Medicine, Departments of Medicine and of Pathology, Brigham and Women's Hospital; and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute\/Brigham and Women's Cancer Center, Boston, MA; and Department of Pathology and Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela","family":"Malinowska-Kolodziej","sequence":"additional","affiliation":[{"name":"From the Center for Sarcoma and Bone Oncology and Ludwig Center for Cancer Research; and Department of Radiology, Dana-Farber Cancer Institute; Harvard Medical School; Division of Translational Medicine, Departments of Medicine and of Pathology, Brigham and Women's Hospital; and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute\/Brigham and Women's Cancer Center, Boston, MA; and Department of Pathology and Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Morgan","sequence":"additional","affiliation":[{"name":"From the Center for Sarcoma and Bone Oncology and Ludwig Center for Cancer Research; and Department of Radiology, Dana-Farber Cancer Institute; Harvard Medical School; Division of Translational Medicine, Departments of Medicine and of Pathology, Brigham and Women's Hospital; and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute\/Brigham and Women's Cancer Center, Boston, MA; and Department of Pathology and Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Qin","sequence":"additional","affiliation":[{"name":"From the Center for Sarcoma and Bone Oncology and Ludwig Center for Cancer Research; and Department of Radiology, Dana-Farber Cancer Institute; Harvard Medical School; Division of Translational Medicine, Departments of Medicine and of Pathology, Brigham and Women's Hospital; and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute\/Brigham and Women's Cancer Center, Boston, MA; and Department of Pathology and Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D.M.","family":"Fletcher","sequence":"additional","affiliation":[{"name":"From the Center for Sarcoma and Bone Oncology and Ludwig Center for Cancer Research; and Department of Radiology, Dana-Farber Cancer Institute; Harvard Medical School; Division of Translational Medicine, Departments of Medicine and of Pathology, Brigham and Women's Hospital; and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute\/Brigham and Women's Cancer Center, Boston, MA; and Department of Pathology and Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Vena","sequence":"additional","affiliation":[{"name":"From the Center for Sarcoma and Bone Oncology and Ludwig Center for Cancer Research; and Department of Radiology, Dana-Farber Cancer Institute; Harvard Medical School; Division of Translational Medicine, Departments of Medicine and of Pathology, Brigham and Women's Hospital; and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute\/Brigham and Women's Cancer Center, Boston, MA; and Department of Pathology and Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azra H.","family":"Ligon","sequence":"additional","affiliation":[{"name":"From the Center for Sarcoma and Bone Oncology and Ludwig Center for Cancer Research; and Department of Radiology, Dana-Farber Cancer Institute; Harvard Medical School; Division of Translational Medicine, Departments of Medicine and of Pathology, Brigham and Women's Hospital; and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute\/Brigham and Women's Cancer Center, Boston, MA; and Department of Pathology and Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina R.","family":"Antonescu","sequence":"additional","affiliation":[{"name":"From the Center for Sarcoma and Bone Oncology and Ludwig Center for Cancer Research; and Department of Radiology, Dana-Farber Cancer Institute; Harvard Medical School; Division of Translational Medicine, Departments of Medicine and of Pathology, Brigham and Women's Hospital; and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute\/Brigham and Women's Cancer Center, Boston, MA; and Department of Pathology and Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikhil H.","family":"Ramaiya","sequence":"additional","affiliation":[{"name":"From the Center for Sarcoma and Bone Oncology and Ludwig Center for Cancer Research; and Department of Radiology, Dana-Farber Cancer Institute; Harvard Medical School; Division of Translational Medicine, Departments of Medicine and of Pathology, Brigham and Women's Hospital; and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute\/Brigham and Women's Cancer Center, Boston, MA; and Department of Pathology and Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George D.","family":"Demetri","sequence":"additional","affiliation":[{"name":"From the Center for Sarcoma and Bone Oncology and Ludwig Center for Cancer Research; and Department of Radiology, Dana-Farber Cancer Institute; Harvard Medical School; Division of Translational Medicine, Departments of Medicine and of Pathology, Brigham and Women's Hospital; and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute\/Brigham and Women's Cancer Center, Boston, MA; and Department of Pathology and Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Kwiatkowski","sequence":"additional","affiliation":[{"name":"From the Center for Sarcoma and Bone Oncology and Ludwig Center for Cancer Research; and Department of Radiology, Dana-Farber Cancer Institute; Harvard Medical School; Division of Translational Medicine, Departments of Medicine and of Pathology, Brigham and Women's Hospital; and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute\/Brigham and Women's Cancer Center, Boston, MA; and Department of Pathology and Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert G.","family":"Maki","sequence":"additional","affiliation":[{"name":"From the Center for Sarcoma and Bone Oncology and Ludwig Center for Cancer Research; and Department of Radiology, Dana-Farber Cancer Institute; Harvard Medical School; Division of Translational Medicine, Departments of Medicine and of Pathology, Brigham and Women's Hospital; and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute\/Brigham and Women's Cancer Center, Boston, MA; and Department of Pathology and Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2007.0035"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2559.2005.02316.x"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2009.05.011"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/01.pas.0000173232.22117.37"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa063564"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/path.2289"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2007.01.028"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-006-0308-9"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nature07179"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204009"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejim.2006.07.017"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-146-9-200705010-00022"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2006.05.018"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2008.08677.x"},{"key":"B15","doi-asserted-by":"crossref","first-page":"521s","DOI":"10.1200\/jco.2006.24.18_suppl.9505","volume":"24","author":"Chawla SP","year":"2006","journal-title":"J Clin Oncol"},{"key":"B16","doi-asserted-by":"crossref","first-page":"521s","DOI":"10.1200\/jco.2006.24.18_suppl.9504","volume":"24","author":"Okuno SH","year":"2006","journal-title":"J Clin Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3800995"}],"container-title":["Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/JCO.2009.25.2981","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T22:57:04Z","timestamp":1653519424000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/JCO.2009.25.2981"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,2,10]]},"references-count":17,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2010,2,10]]}},"alternative-id":["10.1200\/JCO.2009.25.2981"],"URL":"https:\/\/doi.org\/10.1200\/jco.2009.25.2981","relation":{},"ISSN":["0732-183X","1527-7755"],"issn-type":[{"value":"0732-183X","type":"print"},{"value":"1527-7755","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,2,10]]}}}