Poly ADP-ribose polymerase (PARP) inhibitors, including talazoparib, potentiate temozolomide efficacy in multiple tumor types; however, talazoparib-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates talazoparib ± temozolomide in clinically relevant GBM models. Talazoparib at 1–3 nmol/L sensitized T98G, U251, and GBM12 cells to temozolomide, and enhanced DNA damage signaling and G2–M arrest in vitro. In vivo cyclical therapy with talazoparib (0.15 mg/kg twice daily) combined with low-dose temozolomide (5 mg/kg daily) was well tolerated. This talazoparib/temozolomide regimen prolonged tumor stasis more than temozolomide alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days versus 50 days temozolomide (P = 0.005), 11 days placebo (P < 0.001)]. However, talazoparib/temozolomide did not accentuate survival beyond that of temozolomide alone in corresponding orthotopic xenografts [median survival 37 vs. 30 days with temozolomide (P = 0.93), 14 days with placebo, P < 0.001]. Average brain and plasma talazoparib concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49 ± 0.07 ng/g and 25.5±4.1 ng/mL, respectively. The brain/plasma distribution of talazoparib in Bcrp−/− versus wild-type (WT) mice did not differ, whereas the brain/plasma ratio in Mdr1a/b−/− mice was higher than WT mice (0.23 vs. 0.02, P < 0.001). Consistent with the in vivo brain distribution, overexpression of MDR1 decreased talazoparib accumulation in MDCKII cells. These results indicate that talazoparib has significant MDR1 efflux liability that may restrict delivery across the blood–brain barrier, and this may explain the loss of talazoparib-mediated temozolomide sensitization in orthotopic versus heterotopic GBM xenografts. Mol Cancer Ther; 16(12); 2735–46. ©2017 AACR.

中文翻译：

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talazoparib 通过血脑屏障的限制递送限制了聚（ADP-核糖）聚合酶抑制对胶质母细胞瘤中替莫唑胺治疗的敏化作用

聚 ADP-核糖聚合酶 (PARP) 抑制剂，包括 talazoparib，可增强替莫唑胺在多种肿瘤类型中的疗效；然而，尚未在原位胶质母细胞瘤 (GBM) 模型中评估 talazoparib 介导的致敏作用。本研究在临床相关的 GBM 模型中评估了 talazoparib ± 替莫唑胺。1-3 nmol/L 的 Talazoparib 使 T98G、U251 和 GBM12 细胞对替莫唑胺敏感，并增强了体外 DNA 损伤信号和 G2-M 期阻滞。talazoparib（0.15 mg/kg 每天两次）联合低剂量替莫唑胺（5 mg/kg 每天）的体内循环治疗耐受性良好。在异位 GBM12 异种移植物中，这种 talazoparib/替莫唑胺方案比单独使用替莫唑胺更能延长肿瘤停滞时间 [至终点的中位时间：76 天 vs 50 天替莫唑胺 (P = 0.005)，11 天安慰剂 (P < 0.001)]。然而，在相应的原位异种移植物中，他拉唑帕尼/替莫唑胺并没有比单独使用替莫唑胺更能提高生存率 [替莫唑胺组的中位生存时间为 37 天 vs. 30 天 (P = 0.93)，安慰剂组为 14 天，P < 0.001]。单次给药 (0.15 mg/kg) 后 2 小时的平均脑和血浆 talazoparib 浓度分别为 0.49 ± 0.07 ng/g 和 25.5 ±4.1 ng/mL。talazoparib 在 Bcrp−/− 与野生型 (WT) 小鼠中的脑/血浆分布没有差异，而 Mdr1a/b−/− 小鼠的脑/血浆比率高于 WT 小鼠（0.23 对 0.02，P < 0.001)。与体内脑分布一致，MDR1 的过表达减少了 talazoparib 在 MDCKII 细胞中的积累。这些结果表明 talazoparib 具有显着的 MDR1 外排倾向，可能会限制通过血脑屏障的传递，这可以解释在原位与异位 GBM 异种移植物中 talazoparib 介导的替莫唑胺致敏作用的丧失。摩尔癌症治疗; 16(12); 2735-46。©2017 AACR。