Sunitinib malate and figitumumab in solitary fibrous tumor: patterns and molecular bases of tumor response.
Antiangiogenic treatment activity has been reported in solitary fibrous tumor (SFT), a rare and little chemosensitive sarcoma. We explored the activity of sunitinib malate (SM) in SFT and studied receptor tyrosine kinase (RTK) activation profile. Eleven patients with progressive metastatic SFT resistant to chemotherapy were treated with continuous-dosing 37.5 mg/d SM on a named-use basis. One of them also received the insulin-like growth factor I receptor (IGFIR) inhibitor figitumumab after developing secondary resistance to SM. Besides, biochemical, molecular, and fluorescence in situ hybridization analyses were done in eight naïve SFTs whose cryopreserved material was available to clarify RTK upstream and downstream signaling. In two cases treated with SM and belonging to the naïve series, both pretreatment and posttreatment samples were available. Ten patients were evaluable for response to SM. The best response according to the Choi criteria was six partial response (all with Response Evaluation Criteria in Solid Tumors stable disease), one stable disease, and three progressive disease. Responses lasted >6 months in five patients. The eight naïve samples showed high expression/phosphorylation of PDGFRB, epidermal growth factor receptor, and IGFIR/IR, in the presence of their cognate ligands. Downstream pathways revealed expression/activation of Akt, extracellular signal-regulated kinase 1-2 and, closely related to SFT subtypes, of S6 and 4E-BP1. In two patients, whose pretreatment and posttreatment clinical and molecular status were available, biochemical data confirmed the activity of SM, although they also suggested a possible time-dependent shift of dominant RTK from PDGFRB to IGFIR/insulin receptor. A Response Evaluation Criteria in Solid Tumors partial response to figitumumab corroborated these findings. SM has antitumor activity in SFT, possibly through a PDGFRB-mediated mechanism, but treatments with IGFIR/insulin receptor and possibly epidermal growth factor receptor inhibitors are worth testing.
Stacchiotti
Silvia
S
Adult Sarcoma Medical Oncology Unit, Department of Cancer Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Milan, Italy. silvia.stacchiotti@istitutotumori.mi.it
Negri
Tiziana
T
Palassini
Elena
E
Conca
Elena
E
Gronchi
Alessandro
A
Morosi
Carlo
C
Messina
Antonella
A
Pastorino
Ugo
U
Pierotti
Marco A
MA
Casali
Paolo G
PG
Pilotti
Silvana
S
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics*; D018450:Disease Progression; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011758:Pyrroles / Q000008:administration & dosage*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D054364:Solitary Fibrous Tumors / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077210:Sunitinib; D014057:Tomography, X-Ray Computed; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D016756:Immunoglobulins, Intravenous; D007211:Indoles; D011758:Pyrroles; D020797:Receptor, Platelet-Derived Growth Factor beta; D000077210:Sunitinib; C525021:figitumumab