title: Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors.
abstract: PURPOSE 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. PATIENTS AND METHODS 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. Results 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. CONCLUSION 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.
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA. Andrew_Wagner@dfci.harvard.edu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: Izabela
authors.initials: I
authors.lastname: Malinowska-Kolodziej
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Morgan
authors.forename: Wei
authors.initials: W
authors.lastname: Qin
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Natalie
authors.initials: N
authors.lastname: Vena
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Nikhil H
authors.initials: NH
authors.lastname: Ramaiya
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000037:antagonists & inhibitors*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D046912:Multiprotein Complexes; D054973:Perivascular Epithelioid Cell Neoplasms / Q000737:chemistry / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors*; D011506:Proteins; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors / Q000032:analysis / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics; D014481:United States
chemical_list: D000903:Antibiotics, Antineoplastic; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D011506:Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D014157:Transcription Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus