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-激酶信号通路以增强血管靶向光动力疗法的治疗效果

血管靶向光动力疗法 (PDT) 通过诱导对血管系统（尤其是内皮细胞）的氧化损伤来选择性地破坏血管功能。尽管在临床前和临床研究中都充分证明了有效的肿瘤根除和出色的安全性，但已知血管不完全关闭和血管生成会导致血管靶向 PDT 后肿瘤复发。我们已经探索了用 PI3K 信号通路抑制剂增强血管靶向 PDT 的治疗效果，因为 PI3K 通路的激活参与促进 PDT 后内皮细胞的存活和增殖。在这里，PI3K 通路的三种临床相关小分子抑制剂（BYL719、BKM120 和 BEZ235）与维替泊芬-PDT 联合进行了评估。尽管所有三种抑制剂都能够协同增强内皮细胞的 PDT 反应，但 PDT 与双重 PI3K/mTOR 抑制剂 BEZ235 的协同作用最强，其次是与泛 PI3K 抑制剂 BKM120 和 p110α 异构体选择性抑制剂 BYL719 的组合。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，并比单独的每种治疗诱导更多的细胞凋亡。除了增加治疗致死率外，BEZ235 与 PDT 联合有效抑制 PI3K 通路激活和随后的内皮细胞增殖，导致持续的生长抑制。在 PC-3 前列腺肿瘤模型中，联合治疗通过将单独由 PDT 引起的暂时性肿瘤再生延迟转变为更持久的治疗反应来改善治疗结果。我们的研究强烈支持血管靶向 PDT 和 PI3K 通路抑制剂，特别是 mTOR 抑制剂的组合，以增强治疗效果。摩尔癌症治疗; 16(11); 2422-31。©2017 AACR。