Abstract LB-295: Targeted therapy of human osteosarcoma cell lines

Abstract

Abstract A <20% survival rate for metastatic and recurrent osteosarcoma reflects the inadequacy of available therapies. We aimed to [1] investigate the therapeutic effect of a multikinase inhibitor (sorafenib, gift from Bayer) alone or as a radiosensitizor in human osteosarcoma cell lines, [2] establish a 143B orthotopic mouse model of human osteosarcoma with lung metastasis to identify ras down stream signaling pathways, and [3] assess effect of blocking specific pathway on 143B invasion using a MEK/ERK inhibitor (U0126). Osteosarcoma cell lines, 143B (HOS cell line with k-ras oncogene transformation), HOS and U-2 OS were used in an in vitro experiments. The 143B was also used to set up an orthotopic osteosarcoma mouse model. Clonogenic assay was used to assess the anti-cell growth and anti-colony formation effects of sorafenib and/or radiotherapy (Therapax 3 System) respectively. Immunohistochemistry was used to measure ras down stream signaling factors from both local tumor and lung secondaries of the mouse model. A Matrigel assay was used to assess 143B invasion under interference. IC50s for sorafenib (µg/ml) and x-ray (Gy) were 14.98 and 2.72 (143B), 6.52 and 1.48 (HOS) and 7.72 and 1.49 (U-2 OS) respectively. Ras transformed 143B was relatively insensitive to sorafenib monotherapy. Sorafenib can enhance x-ray treatment in HOS (5-26%) and U-2 OS (4-26%), but not in 143B. The 143B was then used to be injected into the left tibia of 15 nude mice and showed tumor mass at both local area and lung. Detection of ras down stream signaling factors, we found that total MEK, Akt, p38 and phosphorylated MEK (p-MEK), but not p-Akt and p-p38 were positive in both local tumors and lung secondaries. Leiomyosarcoma controls expressed p-Akt and p-MEK, but not p-p38. The 143B cells treated with U0126 had significantly lower in vitro invasion ability compared with controls. Our results indicated that sorafenib may enhance radiotherapy in vitro in some of the osteosarcoma cell lines without overexpression of k-ras gene. The Ras/Raf/MEK/ERK, may play an important role in osteosarcoma lung metastasis, and the targeting MEK/ERK by its specific inhibitor may have a potential use in the effective treatment of osteosarcoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-295. doi:1538-7445.AM2012-LB-295