Response to Sunitinib Malate in Advanced Alveolar Soft Part Sarcoma
Silvia Stacchiotti,1ElenaTamborini,2 Andrea Marrari,1Silvia Brich,2 Sara Arisi Rota,2 Marta Orsenigo,2
Flavio Crippa,3 Carlo Morosi,4 Alessandro Gronchi,5 Marco A. Pierotti,2 Paolo G. Casali,1 and Silvana Pilotti2
https://air.unimi.it/retrieve/handle/24 ... 6.full.pdf
https://clincancerres.aacrjournals.org/ ... /15/3/1096
Abstract
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.
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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.
Response to Sunitinib Malate in Advanced Alveolar Soft Part Sarcoma
Response to Sunitinib Malate in Advanced Alveolar Soft Part Sarcoma
Last edited by D.ap on Sun Jun 14, 2020 3:43 am, edited 2 times in total.
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