Children's Cancer Institute, American University of Beirut, Beirut, Lebanon.
Department of Biology, Faculty of Science, EDST, Lebanese University, Beirut, Lebanon.
Int J Cancer. 2016 Mar 15;138(6):1528-37. doi: 10.1002/ijc.29886. Epub 2015 Oct 22.
Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, only moderate improvements in survival have been made for patients with advanced disease. Retinoic acid is a differentiation agent that has shown some antitumor efficacy in RMS cells in vitro; however, the effects are of low magnitude. E-3-(4'-hydroxyl-3'-adamantylbiphenyl-4-yl) acrylic acid (ST1926) is a novel orally available synthetic atypical retinoid, shown to have more potent activity than retinoic acid in several types of cancer cells. We used in vitro and in vivo models of RMS to explore the efficacy of ST1926 as a possible therapeutic agent in this sarcoma. We found that ST1926 reduced RMS cell viability in all tested alveolar (ARMS) and embryonal (ERMS) RMS cell lines, at readily achievable micromolar concentrations in mice. ST1926 induced an early DNA damage response (DDR), which led to increase in apoptosis, in addition to S-phase cell cycle arrest and a reduction in protein levels of the cell cycle kinase CDK1. Effects were irrespective of TP53 mutational status. Interestingly, in ARMS cells, ST1926 treatment decreased PAX3-FOXO1 fusion oncoprotein levels, and this suppression occurred at a post-transcriptional level. In vivo, ST1926 was effective in inhibiting growth of ARMS and ERMS xenografts, and induced a prominent DDR. We conclude that ST1926 has preclinical efficacy against RMS, and should be further developed in this disease in clinical trials.
横纹肌肉瘤（RMS）是儿童中最常见的软组织肉瘤。尽管多次尝试加强化疗治疗方法，但晚期疾病患者的生存率仅得到适度改善。维甲酸是一种分化剂，已在体外 RMS 细胞中显示出一定的抗肿瘤功效；然而，其作用幅度较小。E-3-(4'-羟基-3'-金刚烷-4-基联苯-4-基)丙烯酸（ST1926）是一种新型口服合成非典型维甲酸，已在多种类型的癌细胞中显示出比维甲酸更强的活性。我们使用 RMS 的体外和体内模型来探索 ST1926 作为这种肉瘤的潜在治疗剂的疗效。我们发现 ST1926 在所有测试的肺泡（ARMS）和胚胎（ERMS）RMS 细胞系中均降低 RMS 细胞活力，在小鼠中以易于达到的微摩尔浓度。ST1926 诱导早期 DNA 损伤反应（DDR），除 S 期细胞周期停滞和细胞周期激酶 CDK1 蛋白水平降低外，还导致细胞凋亡增加。作用与 TP53 突变状态无关。有趣的是，在 ARMS 细胞中，ST1926 治疗降低了 PAX3-FOXO1 融合致癌蛋白水平，这种抑制发生在转录后水平。在体内，ST1926 有效抑制 ARMS 和 ERMS 异种移植物的生长，并诱导明显的 DDR。我们得出结论，ST1926 对 RMS 具有临床前疗效，应在临床试验中进一步开发用于治疗该疾病。
