Müller Michael, Rösch Lisa, Najafi Sara, Gatzweiler Charlotte, Ridinger Johannes, Gerloff Xenia F, Jones David T W, Baßler Jochen, Kreth Sina, Stainczyk Sabine, Frese Karen, Meder Benjamin, Westermann Frank, Milde Till, Peterziel Heike, Witt Olaf, Oehme Ina
Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany.
Clinical Cooperation Unit Pediatric Oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Cancers (Basel). 2021 Sep 5;13(17):4476. doi: 10.3390/cancers13174476.
APR-246 (Eprenetapopt/PRIMA-1) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800 cancer cell lines (50 entities; Cancer Therapeutics Response Portal, CTRP) to APR-246 treatment. In particular, neuroblastoma, lymphoma and acute lymphocytic leukemia cells were highly responsive. With gene expression data from the Cancer Cell Line Encyclopedia (CCLE; = 883) and patient samples ( = 1643) from the INFORM registry study, we confirmed that these entities express low levels of a previously described predictive biomarker for APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding APR-246 with approved HDAC-inhibitors, known to elevate ROS, substantially increased APR-246 sensitivity in cell cultures and in vivo in two zebrafish neuroblastoma xenograft models. These data provide evidence that APR-246, in combination with HDAC-inhibitors, displays a novel potent targeted treatment option for neuroblastoma patients.
APR - 246（Eprenetapopt/PRIMA - 1）是一种在临床试验中极具潜力的抗癌药物，最初是作为一种p53重折叠剂开发的。作为一种替代作用模式，有人提出其可提高活性氧（ROS）水平。通过计算机分析，我们研究了大约800种癌细胞系（50个实体；癌症治疗反应门户，CTRP）对APR - 246治疗的反应。特别是神经母细胞瘤、淋巴瘤和急性淋巴细胞白血病细胞反应高度敏感。利用来自癌症细胞系百科全书（CCLE；n = 883）的基因表达数据和INFORM注册研究中的患者样本（n = 1643），我们证实这些实体表达一种先前描述的APR - 246反应性预测生物标志物的低水平。将CTRP药物反应数据与各自的CCLE基因表达谱相结合，我们定义了一种新的基因特征，预测APR - 246治疗有效性的敏感性为90%，特异性为94%。我们在10个细胞系中的8个以及患者样本的体外培养中证实了预测的APR - 246敏感性。此外，在两种斑马鱼神经母细胞瘤异种移植模型中，将阻碍ROS解毒的APR - 246与已知可升高ROS的已批准HDAC抑制剂联合使用，在细胞培养和体内均显著提高了APR - 246的敏感性。这些数据证明，APR - 246与HDAC抑制剂联合使用，为神经母细胞瘤患者提供了一种新的有效靶向治疗选择。
