Vascular-targeted photodynamic therapy (PDT) selectively disrupts vascular function by inducing oxidative damages to the vasculature, particularly endothelial cells. Although effective tumor eradication and excellent safety profile are well demonstrated in both preclinical and clinical studies, incomplete vascular shutdown and angiogenesis are known to cause tumor recurrence after vascular-targeted PDT. We have explored therapeutic enhancement of vascular-targeted PDT with PI3K signaling pathway inhibitors because the activation of PI3K pathway was involved in promoting endothelial cell survival and proliferation after PDT. Here, three clinically relevant small-molecule inhibitors (BYL719, BKM120, and BEZ235) of the PI3K pathway were evaluated in combination with verteporfin-PDT. Although all three inhibitors were able to synergistically enhance PDT response in endothelial cells, PDT combined with dual PI3K/mTOR inhibitor BEZ235 exhibited the strongest synergism, followed in order by combinations with pan-PI3K inhibitor BKM120 and p110α isoform-selective inhibitor BYL719. Combination treatments of PDT and BEZ235 exhibited a cooperative inhibition of antiapoptotic Bcl-2 family protein Mcl-1 and induced more cell apoptosis than each treatment alone. In addition to increasing treatment lethality, BEZ235 combined with PDT effectively inhibited PI3K pathway activation and consequent endothelial cell proliferation after PDT alone, leading to a sustained growth inhibition. In the PC-3 prostate tumor model, combination treatments improved treatment outcomes by turning a temporary tumor regrowth delay induced by PDT alone to a more long-lasting treatment response. Our study strongly supports the combination of vascular-targeted PDT and PI3K pathway inhibitors, particularly mTOR inhibitors, for therapeutic enhancement. Mol Cancer Ther; 16(11); 2422–31. ©2017 AACR .

中文翻译：

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靶向磷脂酰肌醇3-激酶信号通路的血管靶向光动力疗法的治疗性增强。

血管靶向的光动力疗法（PDT）通过诱导对血管系统（尤其是内皮细胞）的氧化损伤，选择性地破坏血管功能。尽管在临床前和临床研究中均已充分证明了有效的肿瘤根除和出色的安全性，但已知不完全的血管关闭和血管生成会导致以血管为靶点的PDT后肿瘤复发。我们已经探索了用PI3K信号通路抑制剂来增强血管靶向PDT的治疗效果，因为PI3K通路的激活与促进PDT后内皮细胞的存活和增殖有关。在此，结合verteporfin-PDT对PI3K途径的三种临床上相关的小分子抑制剂（BYL719，BKM120和BEZ235）进行了评估。尽管所有这三种抑制剂都能协同增强内皮细胞中的PDT反应，但PDT与PI3K / mTOR双重抑制剂BEZ235的结合表现出最强的协同作用，随后依次与pan-PI3K抑制剂BKM120和p110α同工型选择性抑制剂BYL719结合。与单独的每种治疗相比，PDT和BEZ235的联合治疗表现出对抗凋亡Bcl-2家族蛋白Mcl-1的协同抑制作用，并诱导更多的细胞凋亡。除了增加治疗杀伤力外，BEZ235与PDT联合有效地抑制了PI3K途径的活化以及单独使用PDT后内皮细胞的增殖，从而导致了持续的生长抑制。在PC-3前列腺肿瘤模型中，联合治疗通过将仅由PDT引起的暂时性肿瘤再生延迟转变为更持久的治疗反应，从而改善了治疗效果。我们的研究强烈支持以血管靶向的PDT和PI3K途径抑制剂（尤其是mTOR抑制剂）的组合以增强治疗效果。分子癌疗法；16（11）; 2422–31。©2017 AACR。