title: Response to sunitinib malate in advanced alveolar soft part sarcoma.
abstract: OBJECTIVE
  Alveolar soft part sarcoma (ASPS) is a rare, chemoresistant soft tissue sarcoma. ASPS harbors the t(17-X) (p11.2;q25) translocation, resulting in the ASPACR1-TFE3 fusion protein, causing MET autophosphorylation and activation of downstream signaling. The tumor vascular pattern prompted us to use sunitinib malate (SM), a tyrosine kinase inhibitor with antiangiogenic properties.
  
  
  METHODS
  Since July 2007, five patients with progressive metastatic ASPS have been treated with continuous SM 37.5 mg/d on a named basis. Four patients are evaluable for response. In four cases, cryopreserved material was available. Upstream and downstream targets of receptor tyrosine kinase (RTK) pathways, as well as mechanisms of activation, were investigated by biochemical profiles, including human phospho-receptor RTK antibody arrays and immunoprecipitation/Western blotting, molecular analyses, immunohistochemistry, and fluorescence in situ hybridization analyses.
  
  
  RESULTS
  After 3 months, two patients had RECIST (response evaluation criteria in solid tumor) partial response, as well as positron emission tomography response and subjective improvement. One had a RECIST stable disease. One progressed and stopped treatment. One patient is still responding after 12 months. The upstream analysis showed activation of all the platelet-derived growth factor receptor (PDGFR) family members, as well as epidermal growth factor receptor, MET families, and RET. Vascular endothelial growth factor receptors (VEGFR1 and VEGFR2) were activated only in one case. The downstream target analysis showed strong activation of phosphatidylinositol 3-kinase/AKT, extracellular signal-regulated kinase 1/2, and mTOR and its targets (S6K and S6). The absence of any upstream mTOR effector deregulation and the presence of RTK cognate ligands support an autocrine-paracrine activation loop mechanism.
  
  
  CONCLUSIONS
  SM may have antitumor activity in ASPS, possibly through a mechanism involving PDGFR and RET. The role of MET, epidermal growth factor receptor, and mTOR, as well as PDGFR inhibition, needs to be further explored.
authors.affiliation: Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. silvia.stacchiotti@istitutotumori.mi.it
authors.forename: Silvia
authors.initials: S
authors.lastname: Stacchiotti
authors.forename: Elena
authors.initials: E
authors.lastname: Tamborini
authors.forename: Andrea
authors.initials: A
authors.lastname: Marrari
authors.forename: Silvia
authors.initials: S
authors.lastname: Brich
authors.forename: Sara Arisi
authors.initials: SA
authors.lastname: Rota
authors.forename: Marta
authors.initials: M
authors.lastname: Orsenigo
authors.forename: Flavio
authors.initials: F
authors.lastname: Crippa
authors.forename: Carlo
authors.initials: C
authors.lastname: Morosi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gronchi
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Casali
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
mesh_terms: D000328:Adult; D004341:Drug Evaluation; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D018234:Sarcoma, Alveolar Soft Part / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011494:Protein Kinases; C546842:MTOR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000077210:Sunitinib