Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Sevilla, Spain.
Ciber de Cancer, IS Carlos III, Madrid, Spain.
Signal Transduct Target Ther. 2020 Sep 23;5(1):195. doi: 10.1038/s41392-020-00246-z.
Sarcomas constitute a rare heterogeneous group of tumors, including a wide variety of histological subtypes. Despite advances in our understanding of the pathophysiology of the disease, first-line sarcoma treatment options are still limited and new treatment approaches are needed. Histone H2AX phosphorylation is a sensitive marker for double strand breaks and has recently emerged as biomarker of DNA damage for new drug development. In this study, we explored the role of H2AX phosphorylation at Ser139 alone or in combination with MAP17 protein, an inducer of DNA damage through ROS increase, as prognostic biomarkers in sarcoma tumors. Next, we proposed doxorubicin and olaparib combination as potential therapeutic strategies against sarcomas displaying high level of both markers. We evaluate retrospectively the levels of pH2AX (Ser139) and MAP17 in a cohort of 69 patients with different sarcoma types and its relationship with clinical and pathological features. We found that the levels of pH2AX and MAP17 were related to clinical features and poor survival. Next, we pursued PARP1 inhibition with olaparib to potentiate the antitumor effect of DNA damaging effect of the DNA damaging agent doxorubicin to achieve an optimal synergy in sarcoma. We demonstrated that the combination of olaparib and doxorubicin was synergistic in vitro, inhibiting cell proliferation and enhancing pH2AX intranuclear accumulation, as a result of DNA damage. The synergism was corroborated in patient-derived xenografts (PDX) where the combination was effective in tumors with high levels of pH2AX and MAP17, suggesting that both biomarkers might potentially identify patients who better benefit from this combined therapy.
肉瘤是一组罕见的异质性肿瘤，包括多种组织学亚型。尽管我们对疾病的病理生理学有了更多的了解，但一线肉瘤治疗选择仍然有限，需要新的治疗方法。组蛋白 H2AX 磷酸化是双链断裂的敏感标志物，最近已成为新药物开发的 DNA 损伤生物标志物。在这项研究中，我们单独或与 MAP17 蛋白（通过增加 ROS 诱导 DNA 损伤的诱导剂）一起探讨了 H2AX 磷酸化在丝氨酸 139 处的作用，作为肉瘤肿瘤的预后生物标志物。接下来，我们提出多柔比星和奥拉帕利联合治疗作为针对高水平两种标志物的肉瘤的潜在治疗策略。我们回顾性评估了不同肉瘤类型的 69 名患者中 pH2AX（Ser139）和 MAP17 的水平及其与临床和病理特征的关系。我们发现 pH2AX 和 MAP17 的水平与临床特征和不良预后相关。接下来，我们用奥拉帕利抑制 PARP1，以增强 DNA 损伤剂多柔比星的抗肿瘤作用，以在肉瘤中达到最佳协同作用。我们证明奥拉帕利和多柔比星的联合在体外具有协同作用，抑制细胞增殖并增强 pH2AX 核内积累，这是 DNA 损伤的结果。协同作用在患者来源的异种移植（PDX）中得到证实，其中在 pH2AX 和 MAP17 水平较高的肿瘤中，联合治疗有效，这表明这两种生物标志物可能潜在地确定哪些患者从这种联合治疗中获益更多。
