Abstract 5540: Targeting type 1 insulin-like growth factor receptor enhances radiosensitivity in human liposarcoma cell lines

Abstract

Abstract Soft tissue sarcoma (STS) is currently treated by surgery and adjuvant or neoadjuvant radiotherapy. About 20 - 30% of patients develop local recurrence and 50% will eventually die of their disease. Adjuvant cytotoxic therapies improve disease free survival but overall survival is minimally effected. New treatments are required. As with many cancers there is an imbalance between cell growth and cell death and this also the case with STS. Cell growth signals such as those from the insulin-like growth factor receptor (IGF-1R) increases resistance to radiotherapy. We proved that IGF-1R family members are highly expressed in sarcoma tissue samples, particularly IGF-1R 80% positive, which is also significantly associated with histologic grade. This study investigates whether inhibiting IGF-1R can improve the sensitivity of radiotherapy in liposarcomas. Expression of IGF-1R and/or activated IGF-1R in 3 liposarcoma cell lines was detected by western blot and immunoprecipitation respectively. Crystal violet staining and/or clonogenic assays were used to assess anti-proliferative effects of irradiation and IGF-1R inhibitor (tyrphostin AG1024) or IGF-1R downstream pathway inhibitors (LY294002 and SB202190). Irradiation was performed using Therapax DXT300 Orthovoltage Radiation System. We found that the IGF-1R inhibitor can enhance radiotherapy, particularly in the 2 radio-insensitive sarcoma cell lines (combination index <1 = synergism, CI <0.1 for 449B; CI 0.1-0.3 for 778). The drug reduction index (DRI) at IC50 measures how much the dose of x-ray may be reduced when drug and x-ray were combined at the IC50 effect level compared with the dose of x-ray alone. The DRI for 449B and 778 was 3 and 5 fold for x-ray reduction respectively. In addition, we found that radiation can induce activation of IGF-1R in the sarcoma cell line detected with peak time at 4 hours. Using the IGF-1R inhibitor pre-treatment achieved more inhibitory effect than concurrent inhibitor plus X-ray or X-ray alone group. The greatest enhancement of radiosensitivity was observed with pre-treatment of AG1024 followed by combination therapy, resulting in an 80% decrease in cell survival fraction at the highest dose combination. We also used PI3K and p38 pathway inhibitors singly or together compared with the IGF-1R inhibitor in the presence or absence of X-ray or IGF-1 and discovered that both pathways are involved in radioresistance and the inhibition is at least partially IGF-1R dependent. Targeting the IGF-1R to radiosensitize liposarcomas is a novel treatment strategy that can potentially improve the prognosis of some patients with low radiosensitive liposarcoma. 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 5540.