Abstract 589: Expression levels of ABCA6 or ABCA7 predict primary Ewing sarcoma progression at diagnosis

Abstract

Abstract Introduction: Ewing Sarcoma (EWS), the second most common bone tumor occurring in children and young adults, is a clinically very aggressive tumor with high metastatic tendency. EWS therapy is still firmly based on chemotherapy and development of chemoresistance is a major cause of disease progression. The mechanisms of chemoresistance are, however, still poorly defined. In this study, we analyzed the prognostic value of 21 ABC transporters with different mechanisms of action. Materials and methods: Gene expression of 21 ABC transporters was determined by RT-PCR in two different series of EWS patients with primary localized tumor at diagnosis (training set: 30 pts; validation set: 109 pts) and in human EWS cell lines. Association with patient outcome was determined by log-rank test and Kaplan-Meier survival curves (EFS and OVS). Sensitivity to conventional chemotherapeutic agents, such as Doxorubicin, Vincristine, Etoposide, Actinomicin-D and Ifosfamide, was tested in a representative panel of human EWS cell lines. Results: Among the 21 ABC transporters that were analyzed in the training set, expression of ABCA2, ABCA6, ABCA7, ABCB9 and ABCC4 was found to be associated with differential prognosis. Of these genes, only ABCA6 and ABCA7 were confirmed to be significant indicators of EWS progression when the analysis was extended to a new series of 109 patients with localized primary tumor (validation set): high expression of ABCA6 or ABCA7 was associated with a better prognosis. Correlative in vitro studies on EWS cell lines showed that the high expression of ABCA7 was not associated with higher response to conventional drugs, indicating a more complex role in the regulation of EWS aggressiveness. Conclusions: The study validated the impact of ABCA6 or ABCA7, the still poorly understood members of ABC transporters, on EWS progression. However, since high expression of these two transporters is related to better prognosis rather that worse, a different role from the canonical function of drug extruders should be supposed. We are currently testing the association between ABCA7 expression and ceramide levels, which are known to induce cell apoptosis, and macrophage-mediated phagocytosis as indicated in the literature (Kielar D. et al. J Invest Dermatol. 2003 Sep;121(3):465-74; Jehle AW et al. J Cell Biol. 2006 Aug 14;174(4):547-56). Funded by: AIRC to KS IG 14049. Citation Format: Michela Pasello, Marilù Fanelli, Valentina Mularoni, Sonia Ciotti, Piero Picci, Massimo Serra, Katia Scotlandi. Expression levels of ABCA6 or ABCA7 predict primary Ewing sarcoma progression at diagnosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 589. doi:10.1158/1538-7445.AM2015-589