Abstract
Abstract A 5-year 50% survival rate reflects the inadequacy of available therapies. We aimed to investigate the relationship of IGF-1R signaling factor expression with clinicopathological parameters of soft tissue sarcoma (STS) and patient outcome, as well as the therapeutic effect of targeting IGF-1R combined with chemotherapy in sarcoma cell lines. Tissue-microarray and immunohistochemistry were used to detect expression of IGF-1R and its signaling factors, pAkt, pERK, pp38, pJNK and pSTAT3 in 93 samples from 89 STS patients. Combination therapy using IGF-1R inhibitor and each of 5 chemotherapueutic agents was investigated in 11 sarcoma cell lines and analysed by Chou-Talalay method. Mechanism studies were also performed. A strong link between stage and grade with expression of IGF-1R (p<0.033 and p<0.042), pAkt (p<0.004 and p<0.001) and pERK (p=0.002 and p<0.001) in STS was found. Decreased survival correlated with pAkt expression (Multivariate Cox regression p=0.043). Combination treatment of IGF-1R inhibitor with individual chemotherapeutic agents achieved synergistic anti-proliferative effect for all drugs except gemcitabine in some sarcoma cell lines (5/11 carboplatin, 3/11 ifosfamide, 3/11 docetaxel, and 3/11 doxorubicin), accompanied by apoptosis and cytotoxicity. Furthermore, characterisation of IGF-1R signaling interaction by downstream pathway inhibition revealed the importance of activated PI3K and p38 for chemoresistance in a pair of liposarcoma cell lines (synergistic, 778 and antagonistic, SW872). IGF-1R, pAkt and pERK may be predictors of the aggressiveness of STS. IGF-1R inhibition in combination with chemotherapy is a worthwhile strategy to pursue in anti-sarcoma therapy. These results provide a rationale for further clinical evaluation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4416. doi:10.1158/1538-7445.AM2011-4416
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