Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program.
Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program.
复制标题
DOI：
10.1158/1078-0432.ccr-14-2572
复制
发表时间：
2015-02-15
期刊：
影响因子：
--
通讯作者：
Houghton PJ
中科院分区：
文献类型：
--
作者：
Smith MA;Reynolds CP;Kang MH;Kolb EA;Gorlick R;Carol H;Lock RB;Keir ST;Maris JM;Billups CA;Lyalin D;Kurmasheva RT;Houghton PJ
多adp核糖聚合酶（PARP）是一种参与碱基切除修复（BER）的酶，其抑制剂已被证明对同源修复过程中缺乏的肿瘤具有单剂活性。尤文氏肉瘤细胞也对PARP抑制剂敏感，尽管其机制尚不清楚。在这里，我们评估了立体选择性PARP抑制剂talazoparib （BMN 673）与替莫唑胺或拓扑替康联合使用。Talazoparib在体外与替莫唑胺（0.3 - 1000 μmol/L）或topotecan （0.03-100 nmol/L）联合给药，体内给药剂量为0.1 mg/kg，每日2次，连用替莫唑胺（30 mg/kg/每日x 5，组合a）或0.25 mg/kg，每日2次，连用替莫唑胺（12 mg/kg/每日x 5，组合B）。在体外，talazoparib将替莫唑胺的毒性增强了85倍，在尤文氏肉瘤和白血病系中有明显的增强作用（30 - 50倍）。拓扑替康的增强作用较小。在体内，talazoparib增强了替莫唑胺的毒性，组合A和组合B分别代表了与低剂量或高剂量talazoparib联合时的最大耐受剂量。两种组合对10例异种移植尤文氏肉瘤中的5例显示出显著的协同作用。该组合对大多数其他异种移植物模型显示出适度的活性。药效学研究显示，仅在对talazoparib单用或talazoparib联合替莫唑胺敏感的肿瘤模型中，治疗导致PARP完全丧失。talazoparib +替莫唑胺在异种尤文氏肉瘤移植中观察到的高水平活性使其成为儿科评估中考虑的一个有趣的组合。
Inhibitors of poly-ADP ribose polymerase (PARP), an enzyme involved in base excision repair (BER) have demonstrated single agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here we evaluated the stereo-selective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan. Talazoparib was tested in vitro in combination with temozolomide (0.3–1,000 μmol/L) or topotecan (0.03-100 nmol/L) and in vivo at a dose of 0.1 mg/kg administered twice daily for 5 days combined with temozolomide (30 mg/kg/daily x 5; combination A) or 0.25 mg/kg administered twice daily for 5 days combined with temozolomide (12 mg/kg/daily x 5; combination B). In vitro talazoparib potentiated the toxicity of temozolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30–50-fold). There was less potentiation for topotecan. In vivo, talazoparib potentiated the toxicity of temozolomide, and Combination A and Combination B represent the maximum tolerated doses when combined with low dose or high dose talazoparib, respectively. Both combinations demonstrated significant synergism against 5 of 10 Ewing sarcoma xenografts. The combination demonstrated modest activity against most other xenograft models. Pharmacodynamic studies showed a treatment-induced complete loss of PARP only in tumor models sensitive to either talazoparib alone or talazoparib plus temozolomide. The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation.