Online Archive of University of Virginia Scholarship
The VEGF Signaling Axis in Focused Ultrasound Blood Tumor Barrier Opening30 views
Author
Breza, Victoria, Biomedical Engineering - School of Engineering and Applied Science, University of Virginia0000-0003-2294-7222
Advisors
Price, Richard, EN-Biomed Engr Dept, University of Virginia
Abstract
Glioblastoma (GBM) accounts for 40-50% of newly diagnosed primary brain tumors, and current clinical outcomes for patients remain poor. Severe limitations to therapeutic efficacy are due to both the blood-brain and blood-tumor barriers (BBB/BTB). Focused ultrasound (FUS) is a promising tool for enhanced drug delivery, but studies exploring how the uniformity of delivery can be enhanced and how tumor blood vessels impact FUS-mediated delivery are limited. Currently, anti-angiogenic therapy is used in the care of recurrent GBM patients, however high toxicities and limited therapeutic benefits have been observed. The vascular normalization hypothesis posits that low-dose anti-angiogenic therapy, such as inhibition of the vascular endothelial growth factor (VEGF) pathway via VEGF-A (VEGF) or VEGF receptor-2 (VEGFR2) inhibition, can restore the structure and function of tumor vessels without causing significant vascular pruning. We hypothesize that pre-treatment of the tumor vasculature with VEGF pathway inhibition can be leveraged to enhance FUS-mediated model drug delivery using quantitative magnetic resonance imaging (MRI) methods. To explore this hypothesis, I will first employ T1 mapping MRI to quantitate the concentration of two different molecular weight gadolinium-based model drugs in conjunction with a VEGF receptor 2 (VEGFR2) inhibitor, DC101, with and without FUS BTB disruption. I will emphasize assessing concentration, passive cavitation detection (PCD) acoustic emissions, and radiomic feature extraction over the treatment time course to identify a therapeutic window for combined DC101 and FUS. I will then shift to assess how the clinically observed acute vascular normalizing effects with VEGF inhibitor, bevacizumab, can be harnessed to augment FUS BTB opening to enhance delivery using an analogous VEGF inhibiting antibody, aVEGF. The overall goal of this dissertation is to develop combination treatment strategies that enhance FUS via vascular pre-treatment, as well as characterize how dysregulated vessels within the tumor microenvironment may impact effective FUS BTB opening.
Degree
PHD (Doctor of Philosophy)
Keywords
Glioblastoma; Focused Ultrasound; Vascular Remodeling; Drug Delivery; Blood Brain Barrier; Magnetic Resonance Imaging; Brain Cancer
Breza, Victoria. The VEGF Signaling Axis in Focused Ultrasound Blood Tumor Barrier Opening. University of Virginia, Biomedical Engineering - School of Engineering and Applied Science, PHD (Doctor of Philosophy), 2025-12-09, https://doi.org/10.18130/4pdv-zy69.
