Response to Sunitinib Malate in Advanced Alveolar Soft Part Sarcoma
Autor: | Sara Arisi Rota, Flavio Crippa, Silvia Brich, Paolo G. Casali, Andrea Marrari, Carlo Morosi, Marta Orsenigo, Elena Tamborini, Alessandro Gronchi, Silvana Pilotti, Silvia Stacchiotti, Marco A. Pierotti |
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Přispěvatelé: | Stacchiotti, Silvia, Tamborini, Elena, Marrari, Andrea, Brich, Silvia, Rota, Sara Arisi, Orsenigo, Marta, Crippa, Flavio, Morosi, Carlo, Gronchi, Alessandro, Pierotti, Marco A., Casali, Paolo G., Pilotti, Silvana |
Rok vydání: | 2009 |
Předmět: |
Adult
Male Cancer Research Indoles Oncology P70-S6 Kinase 1 Receptor tyrosine kinase Growth factor receptor Alveolar soft part sarcoma Sunitinib medicine Humans Pyrroles Receptors Platelet-Derived Growth Factor Epidermal growth factor receptor Phosphorylation Protein Kinase Inhibitors biology TOR Serine-Threonine Kinases Receptor Protein-Tyrosine Kinases Middle Aged Sunitinib malate medicine.disease ErbB Receptors Receptors Vascular Endothelial Growth Factor Sarcoma Alveolar Soft Part Cancer research biology.protein Drug Evaluation Female Protein Kinases Proto-Oncogene Proteins c-akt Platelet-derived growth factor receptor Signal Transduction medicine.drug |
Zdroj: | Clinical Cancer Research. 15:1096-1104 |
ISSN: | 1557-3265 1078-0432 |
DOI: | 10.1158/1078-0432.ccr-08-2050 |
Popis: | Purpose: 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. Experimental Design: 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. Conclusion: 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. |
Databáze: | OpenAIRE |
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