DDEL-26. Modulation of the Blood-Tumor Barrier Using Small-Molecule Inhibitors: Enhancing Chemotherapeutic Penetration in Glioblastoma Therapy

Abstract Efficient drug delivery in glioblastoma (GBM) treatment remains a significant challenge due to the restrictive properties of the blood-brain barrier (BBB) and blood-tumor barrier (BTB). We previously identified a transcriptional signature associated with the BTB, highlighting CDH5 (vascular endothelial cadherin) as a critical regulatory molecule highly expressed in GBM vasculature. Our comprehensive analyses, utilizing bulk RNA sequencing and spatial transcriptomics, confirmed the selective enrichment of CDH5 and associated genes specifically within tumor-associated endothelial cells compared to healthy brain tissue. Mechanistically, our data demonstrate that the indirubin derivative 6-bromoindirubin acetoxime (BIA) significantly downregulates CDH5 expression along with other pivotal genes identified within the BTB signature, including ACVRL1, ENG, and CD93. This molecular modulation effectively disrupts endothelial barrier integrity, as evidenced by reduced trans-endothelial electrical resistance and increased dextran permeability in vitro, alongside enhanced intratumoral sodium fluorescein and cisplatin accumulation in vivo in murine GBM xenograft models. Treatment with BIA notably augmented the therapeutic efficacy of cisplatin by increasing DNA damage, resulting in significant extension of survival in preclinical mouse models compared to monotherapy. Given BIA’s limited clinical translational potential, we are actively investigating FDA-approved kinase inhibitors, such as dasatinib, as viable therapeutic alternatives. Preliminary experiments indicate that dasatinib similarly disrupts BTB integrity and facilitates enhanced chemotherapeutic penetration into GBM tumors. Ongoing studies are rigorously assessing dasatinib’s preclinical efficacy and potential clinical translation, specifically evaluating its impact on therapeutic drug delivery, safety, and effectiveness. Collectively, our research underscores targeted BTB modulation as a promising therapeutic strategy, leveraging both novel agents such as BIA and repurposed FDA-approved drugs like dasatinib, to significantly enhance therapeutic outcomes, overcome drug delivery barriers, and ultimately improve the prognosis and quality of life for GBM patients.