Ultrasound-mediated thermal stress can provide unique opportunities for treating brain cancer. High temperature focal hyperthermia (> 45 °C) and ablation therapy (> 70°C) can directly destroy cancer cells, whereas mild hyperthermia, which is the focus of this proposal, utilizes mild temperatures (38 – 42 °C) to target brain cancer. A number of studies in peripheral tumors have shown that mild hyperthermia can modify he tumor microenvironment and enable new treatment paradigms towards improving outcomes. Despite progress, the potential and impact of mild hyperthermia in the treatment of brain cancer remains largely unexplored, presumably due to challenges in applying safely hyperthermia in the brain.
The overall objective of the project is to investigate the impact of Magnetic Resonance Imaging guided Focused Ultrasound (MRgFUS) sub-ablative thermal stress (mild-hyperthermia) on brain tumor microenvironment (TME) and its implications to the treatment of glioblstoma (GBM). The specific aims of this research are the following: 1) to design an MRgFUS system that can safely apply trans-skull hyperthermia at desired temperature inside the brain of rodents; 2) to characterize heat-mediated changes in the brain tumor microenvironment (TME), 3) assess its potential to promote the effective release and delivery of thermosensitive drugs (e.g., TSL-Dox); and 4) to assess its abilities to promote therapeutic trafficking of cytotoxic immune T cells (e.g., chimeric antigen receptor T cells (CAR T)) in brain TME.
Overall, this work will help refining our understanding on the role of thermal stress on brain TME and provide new insights on how mild hyperthermia can transiently affect the brain tumor microenvironment and support new treatment paradigms. Demonstration of improving the localized delivery of systemically administered nano-formulated drugs and CAR-T cells with clinically relevant FUS technology will support the potential of the proposed therapeutic strategies for treating brain tumors. Improved therapeutic outcomes by the proposed strategies will support the advancement of this technology to the clinic and towards improving outcomes in patients with aggressive intracranial malignancies, such as GBM.