Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect.
BACKGROUND
The purpose of this study was to confirm sunitinib activity in alveolar soft part sarcoma (ASPS) and to report on new insights into the molecular bases thereof.


METHODS
From July 2007, nine patients with progressive metastatic ASPS received sunitinib 37.5 mg/day, within a named use program. Cryopreserved material was available for five naive patients, among whom three received sunitinib. Immunofluorescence (IF)/confocal microscopy, biochemical, and molecular/cytogenetic analyses were carried out, complemented by antiproliferative and activation assays in a short-term culture derived from one case.


RESULTS
All patients were eligible for response. Best RECIST response was partial response in five cases, stable disease in three, and progression in one. The median progression-free survival was 17 months. Positron emission tomography results were consistent. Two cases of interval progressions were recorded. Antiproliferative assays and biochemistry on short-term culture showed that sunitinib is able to markedly impair ASPS cells growth and switch-off PDGFRB. IF/confocal microscopy demonstrated coexpression and physical association between PDGFRB/vascular endothelial growth factor receptor 2 (VEGFR2) and RET/VEGFR2 in ASPS cells, which was validated by biochemistry. PDGFRB, RET, and MET ligand-dependent activation was confirmed.


CONCLUSIONS
We confirm the clinical efficacy of sunitinib in ASPS, mediated by PDGFRB, VEGFR2, and RET, which are all expressed in tumor cells. A direct antitumor effect was shown in a short-term cell culture.
Department of Cancer Medicine. Electronic address: silvia.stacchiotti@istitutotumori.mi.it.
S
S
Stacchiotti
Department of Pathology, Laboratory of Experimental Molecular Pathology.
T
T
Negri
Department of Experimental Oncology and Molecular Medicine.
N
N
Zaffaroni
Department of Cancer Medicine.
E
E
Palassini
Department of Radiology.
C
C
Morosi
Department of Pathology, Laboratory of Experimental Molecular Pathology.
S
S
Brich
Department of Pathology, Laboratory of Experimental Molecular Pathology.
E
E
Conca
Department of Pathology, Laboratory of Experimental Molecular Pathology.
F
F
Bozzi
Department of Experimental Oncology and Molecular Medicine.
G
G
Cassinelli
Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
A
A
Gronchi
Department of Cancer Medicine.
P G
PG
Casali
Department of Pathology, Laboratory of Experimental Molecular Pathology.
S
S
Pilotti
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D018234:Sarcoma, Alveolar Soft Part / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000077210:Sunitinib; D015996:Survival Rate; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib