title: Temsirolimus in advanced leiomyosarcomas: patterns of response and correlation with the activation of the mammalian target of rapamycin pathway.
abstract: Preclinical data have indicated that alteration of PTEN and activation of the mammalian target of rapamycin (mTOR) pathway play a crucial role in the oncogenesis of leiomyosarcoma. The objective of this exploratory study was to assess the clinical role of mTOR inhibition in patients with advanced leiomyosarcoma refractory to standard chemotherapy. Patients with advanced leiomyosarcoma were treated with temsirolimus and consented to retrospective collection of data from their medical records and analysis of archival tumor specimens. Tumor response was determined according to the response evaluation criteria in solid tumor (RECIST) and Choi criteria. Tumors were assessed for immunohistochemical evidence of PTEN loss of expression and mTOR activation. Six patients participated in the study. According to the RECIST, three patients had stable disease and three patients had progressive disease. The three patients with RECIST stable disease had partial response according to the Choi criteria. Partial response according to the Choi criteria was associated with clinical improvement and biological signs of temsirolimus antitumor activity. The immunohistochemical status of PTEN and phosphorylated S6 ribosomal protein was not predictive of the outcome. This exploratory study indicates antitumor activity of temsirolimus in leiomyosarcoma, possibly through a mechanism involving aberration of the PTEN gene. Further investigations of the phosphoinositide 3-kinases/PTEN/Akt/mTOR pathway are needed to explore the role of mTOR inhibitors, either alone or in combination, in patients with advanced sarcoma.
authors.affiliation: Department of Medical Oncology, Institut Bergonié, Bordeaux, Cedex, France. italiano@bergonie.org
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
authors.forename: Michèle
authors.initials: M
authors.lastname: Kind
authors.forename: Eberhard
authors.initials: E
authors.lastname: Stoeckle
authors.forename: Natalie
authors.initials: N
authors.lastname: Jones
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.forename: Binh
authors.initials: B
authors.lastname: Bui
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D038601:Ribosomal Protein S6 / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013223:Statistics as Topic; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D038601:Ribosomal Protein S6; C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus