Flow-informed therapy for glioblastoma - Project Summary Glioblastoma is a deadly brain cancer marked by extensive invasion into the surrounding brain. Interstitial fluid flow is heightened during disease development and is a major driver of tumor progression. These fluid flows in and around brain tumors are heterogeneous and can be mapped by using our mathematical modeling approach that uses a single patient or mouse’s dynamic MRI to generate 3D maps of interstitial transport quickly and robustly. Interstitial flow not only changes during tumor progression, but can also change in response to anti- tumor therapy, but the ways in which this happens and the dynamism of these changes are relatively unknown. Here we propose to focus on interstitial fluid flow in glioblastoma to target treatments, assess treatment efficacy, and plan treatment using a range of in vivo and mathematical modeling tools alongside advanced engineering and imaging methodology. First, we will leverage the finding that interstitial fluid flow and transport can be used to identify invading tumor cells to target treatment via focused ultrasound mediated blood brain barrier opening, developing a novel precise FUS system coupled with both validation and treatment to target invasive tumor cells preclinically on demand. Next, we will develop methodology to compare flow fields over the course of a series of standard of care treatments (temozolomide and radiation therapy), physical drug delivery methods (convection enhanced delivery and focused ultrasound), and antibody based targeted therapies (anti-VEGF and anti-PD1). In this way, we will assess the changes to flow acutely and longitudinally and correlate these outcomes with tumor growth and progression. Last, we will leverage advanced computational methods to use initial interstitial flow fields and transport metrics to map drug delivery and disease progression. Founded on our basis of preliminary data we will create physics-based mathematical models to determine the best flow directed therapeutic strategies and will validate our approach with in vivo studies. Overall, this work leverages an untapped biophysical biomarker, interstitial fluid flow, in glioblastoma to target treatment, understand treatment responses, and plan treatment. With this new understanding of the dynamics and significance of interstitial fluid flow in treatment of GBM, we can translate our methodologies and outcomes to patients.
