Abstract
Abstract A static 50% 5-year overall survival rate reflects inadequacy of currently available therapies and urgent need to develop treatment strategies for sarcoma. Single epidermal growth factor receptor (EGFR) inhibitor, gefitinib was reported in a phase II trial in synovial sarcoma with a low response rate and short sustained time. Identification of combinations with both a higher proportion of responders and potentially more sustained benefit is needed. One potential partner is interferon-alpha. We have shown in vitro that cell growth signals such as those from an activated EGFR increases resistance to interferon-alpha, and the combination of EGFR inhibitor and interferon-alpha has synergistic antitumor effect in some colon and bladder cancer cell lines. A recent phase II trial of gefitinib and pegylated interferon alfa 2b in previously-treated renal cell carcinoma has demonstrated significant and prolonged disease control benefit with acceptable toxicity. However the effect of the combination therapy in sarcoma is unreported. This study aimed to investigate the effect and mechanisms of this combination therapy in human sarcoma cell lines. Combination treatment using gefitinib and interferon-alpha was investigated in a panel of sarcoma cell lines (6 soft tissue sarcomas (STS) and 3 osteosarcomas (OS)) with synergy analysis based on the Chou-Talalay combination index. Mechanism studies examined a pair of synergistic and antagonistic liposarcoma cell lines using multiple techniques. All 9 cell lines expressed wild-type and/or activated EGFR and interferon-alpha receptors but no EGFR gene mutation was identified. Combination treatment of EGFR inhibition and interferon-alpha achieved synergistic antiproliferative effect (combination index (CI) <1 = synergism) in 6/9 sarcoma cell lines (CI for STS: GCT 0.1-0.3, SW684 0.3-0.7, and 778 0.1-0.7; for OS: MG63 0.3-0.7, U2OS 0.3-0.7, and SJSA 0.1-0.3), accompanied by apoptotic and necrotic cell death. The drug reduction index (DRI) at IC50 measures how much the dose of each drug may be reduced when drugs were combined at the IC50 effect level compared with the dose of drug alone. For the most synergistic GCT cell line, the DRI for gefitinib and interferon-alpha was 4.7 and >100. Characterisation of interferon-alpha and EGFR signaling interaction by both pathway inhibition and western blot detection of downstream factor expression discovered that interferon-alpha enhances gefitinib through affecting the ratio of the signal transducer and activator of transcription (STAT) family members (STAT1 up, STAT3 down) to favour tumor cell death. The activated Akt enhanced by interferon-alpha alone was significantly down regulated by combination therapy. EGFR inhibition combined with interferon-alpha is a worthwhile treatment to pursue in anti-sarcoma therapy. These results provide a rationale for the clinical evaluation of this treatment strategy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1655.
Published Version
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