Mittapalli Rajendar K, Chung Alexander H, Parrish Karen E, Crabtree Donna, Halvorson Kyle G, Hu Guo, Elmquist William F, Becher Oren J
Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota.
Department of Pediatrics, Duke University, Durham, North Carolina. Department of Pathology, Duke University, Durham, North Carolina. Preston Robert Tisch Brain Tumor Center, Durham, North Carolina.
Mol Cancer Ther. 2016 May;15(5):819-29. doi: 10.1158/1535-7163.MCT-15-0093. Epub 2016 Feb 16.
Dasatinib is a multikinase inhibitor in clinical trials for glioma, and thus far has failed to demonstrate significant efficacy. We investigated whether the ABC efflux transporters ABCG2 and ABCB1 expressed in the blood-brain barrier (BBB), are limiting the efficacy of dasatinib in the treatment of glioma using genetic and pharmacologic approaches. We utilized a genetic brainstem glioma mouse model driven by platelet-derived growth factor-B and p53 loss using abcg2/abcb1 wild-type (ABC WT) or abcg2/abcb1 knockout mice (ABC KO). First, we observed that brainstem glioma tumor latency is significantly prolonged in ABC KO versus ABC WT mice (median survival of 47 vs. 34 days). Dasatinib treatment nearly doubles the survival of brainstem glioma-bearing ABC KO mice (44 vs. 80 days). Elacridar, an ABCG2 and ABCB1 inhibitor, significantly increases the efficacy of dasatinib in brainstem glioma-bearing ABC WT mice (42 vs. 59 days). Pharmacokinetic analysis demonstrates that dasatinib delivery into the normal brain, but not into the tumor core, is significantly increased in ABC KO mice compared with ABC WT mice. Surprisingly, elacridar did not significantly increase dasatinib delivery into the normal brain or the tumor core of ABC WT mice. Next, we demonstrate that the tight junctions of the BBB of this model are compromised as assessed by tissue permeability to Texas Red dextran. Finally, elacridar increases the cytotoxicity of dasatinib independent of ABCG2 and ABCB1 expression in vitro In conclusion, elacridar improves the efficacy of dasatinib in a brainstem glioma model without significantly increasing its delivery to the tumor core. Mol Cancer Ther; 15(5); 819-29. ©2016 AACR.
达沙替尼是一种正在进行胶质瘤临床试验的多激酶抑制剂，但迄今为止尚未显示出显著疗效。我们研究了血脑屏障（BBB）中表达的ABC外排转运蛋白ABCG2和ABCB1是否使用基因和药理学方法限制了达沙替尼治疗胶质瘤的疗效。我们利用了由血小板衍生生长因子-B和p53缺失驱动的遗传性脑干胶质瘤小鼠模型，使用abcg2/abcb1野生型（ABC WT）或abcg2/abcb1敲除小鼠（ABC KO）。首先，我们观察到与ABC WT小鼠相比，ABC KO小鼠的脑干胶质瘤肿瘤潜伏期显著延长（中位生存期分别为47天和34天）。达沙替尼治疗使携带脑干胶质瘤的ABC KO小鼠的生存期几乎翻倍（44天对80天）。ABCG2和ABCB1抑制剂艾拉司群显著提高了达沙替尼对携带脑干胶质瘤的ABC WT小鼠的疗效（42天对59天）。药代动力学分析表明，与ABC WT小鼠相比，ABC KO小鼠中达沙替尼向正常脑内的递送显著增加，但向肿瘤核心的递送未显著增加。令人惊讶的是，艾拉司群并未显著增加达沙替尼向ABC WT小鼠正常脑或肿瘤核心的递送。接下来，我们证明，通过对Texas Red葡聚糖的组织通透性评估，该模型血脑屏障的紧密连接受损。最后，艾拉司群在体外增加了达沙替尼的细胞毒性，且与ABCG2和ABCB1的表达无关。总之，艾拉司群在脑干胶质瘤模型中提高了达沙替尼的疗效，但未显著增加其向肿瘤核心的递送。《分子癌症治疗》；15（5）；819 - 29。©2016美国癌症研究协会。
