PO.ET05.03 · 实验与分子治疗
靶向调控血-肿瘤屏障增强胶质母细胞瘤模型中的药物递送和生存
Targeted modulation of the blood-tumor barrier enhances drug delivery and survival in glioblastoma models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
由于血脑屏障和血-肿瘤屏障（BBB/BTB）的限制性特性，胶质母细胞瘤（GBM）中的高效药物递送仍然是一项重大的治疗挑战。我们此前识别出一个BTB相关转录特征，突出显示CDH5（血管内皮钙黏蛋白）是一个在GBM血管系统中高表达的关键调控分子。使用bulk RNA测序和空间转录组学，我们证实与健康脑组织相比，CDH5及其相关基因在肿瘤相关内皮细胞中选择性富集。在机制上，我们显示靛玉红衍生物6-溴靛玉红-3'-乙酰肟（BIA）显著下调CDH5及其他BTB特征基因，包括ACVRL1、ENG和CD93。这种分子调控破坏了内皮屏障完整性，表现为体外跨内皮电阻降低和葡聚糖通透性增加，以及在小鼠GBM异种移植模型中体内瘤内荧光素钠和顺铂蓄积增强。BIA治疗通过增加DNA损伤进一步增强了顺铂的疗效，与单药治疗相比显著延长了生存。为探究潜在机制，我们正在评估BIA对参与BBB调控的转录因子（包括CREB和ERG）以及对细胞骨架动力学的影响。鉴于BIA是一种广谱激酶抑制剂，转化潜力有限，我们正在积极评估FDA批准的激酶抑制剂（如达沙替尼）作为可快速转化的临床可行替代方案。初步数据表明达沙替尼同样破坏BTB完整性并增强化疗药物向GBM肿瘤的渗透。正在进行的研究正在测试达沙替尼的临床前疗效，特别是其对药物递送、安全性和治疗有效性的影响。总体而言，这些发现将靶向BTB调控确立为一种有前景的治疗策略。同时利用BIA等新型药物和达沙替尼等再利用的FDA批准药物，可能显著增强药物递送、改善治疗结局，并最终使GBM患者获益。
查看英文原文 English abstract
Efficient drug delivery in glioblastoma (GBM) remains a major therapeutic challenge due to the restrictive properties of the blood-brain and blood-tumor barriers (BBB/BTB). We previously identified a BTB-associated transcriptional signature highlighting CDH5 (vascular endothelial cadherin) as a critical regulatory molecule highly expressed in GBM vasculature. Using bulk RNA sequencing and spatial transcriptomics, we confirmed that CDH5 and its associated genes are selectively enriched in tumor-associated endothelial cells compared with healthy brain tissue. Mechanistically, we show that the indirubin derivative 6-bromoindirubin acetoxime (BIA) significantly downregulates CDH5 and additional BTB-signature genes, including ACVRL1, ENG, and CD93. This molecular modulation disrupts endothelial barrier integrity, demonstrated by reduced trans-endothelial electrical resistance and increased dextran permeability in vitro, as well as enhanced intratumoral sodium fluorescein and cisplatin accumulation in vivo in murine GBM xenograft models. BIA treatment further augments cisplatin efficacy by increasing DNA damage, resulting in significantly extended survival compared with monotherapy. To investigate underlying mechanisms, we are assessing the effects of BIA on transcription factors involved in BBB regulation (including CREB and ERG) and on cytoskeletal dynamics. Given that BIA is a broad-spectrum kinase inhibitor with limited translational potential, we are actively evaluating FDA-approved kinase inhibitors, such as dasatinib. as clinically viable alternatives for rapid translation. Preliminary data indicate that dasatinib similarly disrupts BTB integrity and enhances chemotherapeutic penetration into GBM tumors. Ongoing studies are testing dasatinib's preclinical efficacy, specifically its impact on drug delivery, safety, and therapeutic effectiveness. Collectively, these findings position targeted BTB modulation as a promising therapeutic strategy. Leveraging both novel agents such as BIA and repurposed FDA-approved drugs like dasatinib may significantly enhance drug delivery, improve therapeutic outcomes, and ultimately benefit patients with GBM.
利益披露 Disclosure
P. C. Vaughn-Beaucaire, None.
B. Wu,
Cytodigm Employment.