Restricted Delivery of Talazoparib Across the Blood-Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma.
Restricted Delivery of Talazoparib Across the Blood-Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma.
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DOI：
10.1158/1535-7163.mct-17-0365
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发表时间：
2017-12
影响因子：
5.7
通讯作者：
Sarkaria JN
中科院分区：
文献类型：
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作者：
Kizilbash SH;Gupta SK;Chang K;Kawashima R;Parrish KE;Carlson BL;Bakken KK;Mladek AC;Schroeder MA;Decker PA;Kitange GJ;Shen Y;Feng Y;Protter AA;Elmquist WF;Sarkaria JN
聚（ADP-核糖）聚合酶PARP抑制剂，包括talazoparib（TAL），可增强替莫唑胺（TMZ）在多种肿瘤类型中的疗效，但尚未在原位胶质母细胞瘤（GBM）模型中评价TAL介导的致敏作用。本研究评价了临床相关GBM模型中的TAL ± TMZ。1-3 nmol/L TAL对TMZ有增敏作用，并能增强TMZ对T98 G、U251和GBM 12细胞的DNA损伤信号，使细胞阻滞于G2/M期。TAL（0.15 mg/kg，每日两次）联合低剂量TMZ（5 mg/kg，每日一次）的体内周期性治疗耐受性良好。在异位GBM 12异种移植物中，该TAL/TMZ方案比单独的TMZ更延长肿瘤停滞[至终点的中位时间：76天对比TMZ 50天（p=0.005），安慰剂11天（p <0.001）]。然而，在相应的原位异种移植物中，TAL/TMZ并没有使存活率超过单独的TMZ（中值存活37天对TMZ的30天（p=0.93），安慰剂的14天，p<0.001）。单次给药（0.15 mg/kg）后2小时的平均脑和血浆TAL浓度分别为0.49±0.07 ng/g和25.5±4.1 ng/ml。Bcrp−/−与WT小鼠中TAL的脑/血浆分布无差异，而Mdr 1a/B−/−小鼠的脑/血浆比高于WT小鼠（0.23 vs. 0.02，p<0.001）。与体内脑分布一致，MDR 1的过表达降低了MDCKII细胞中TAL的蓄积。这些结果表明，TAL具有显著的MDR 1外排倾向，这可能会限制穿过血脑屏障的递送，这可能解释了原位与异位GBM异种移植物中TAL介导的TMZ致敏性的丧失。
Poly (ADP-ribose) polymerase PARP inhibitors, including talazoparib (TAL), potentiate temozolomide (TMZ) efficacy in multiple tumor types, however TAL-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates TAL ± TMZ in clinically relevant GBM models. TAL at 1–3 nmol/L sensitized T98G, U251 and GBM12 cells to TMZ, and enhanced DNA damage signaling and G2/M arrest in vitro. In vivo cyclical therapy with TAL (0.15 mg/kg twice daily) combined with low dose TMZ (5 mg/kg daily) was well tolerated. This TAL/TMZ regimen prolonged tumor stasis more than TMZ alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days vs. 50 days TMZ (p=0.005), 11 days placebo (p <0.001)]. However, TAL/TMZ did not accentuate survival beyond that of TMZ alone in corresponding orthotopic xenografts (median survival 37 vs. 30 days with TMZ (p=0.93), 14 days with placebo, p<0.001). Average brain and plasma TAL 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 TAL in Bcrp−/− versus WT mice did not differ, while 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 TAL accumulation in MDCKII cells. These results indicate that TAL has significant MDR1 efflux liability that may restrict delivery across the blood-brain barrier, and this may explain the loss of TAL-mediated TMZ sensitization in orthotopic versus heterotopic GBM xenografts.