SUMMARY

Characterization and monitoring of brain cancer response to treatment is critical for effective therapy. Current assessment of brain tumors is based either on imaging (MRI), which provides only gross information about tumor progression (e.g. size), or invasive and risky surgical procedures that provide limited spatial sampling that is restricted to a few timepoints. Liquid biopsy is a minimally invasive technique that uses cell-free DNA (cfDNA), in blood samples, to monitor tumor growth and response treatment at a molecular level. While this method is becoming increasingly important for clinical decisions across a range of tumors, in brain tumors it is particularly limited due to inherent challenges associated with the presence of the Blood-Brain Barrier - a semipermeable biological interface that tightly regulates the transport of macromolecules between the tumor core and the bloodstream. Although in brain tumors the BBB is compromised, its permeability is highly heterogeneous and still restricts the transport of molecules.
Microbubble-enhanced focused ultrasound (MB-FUS) is a tunable technology that can reversibly open the BBB and enhance the transport of macromolecules across the BBB between the circulatory system and the tumor microenvironment. This technology is currently under clinical evaluation for improving the delivery of anticancer agents in brain tumors. There lies the opportunity to combine MB-FUS with liquid biopsy techniques to assess BBB opening, monitor disease progression, and estimate response to treatment. The proposed research will provide insights about the rate limiting biological variables and establish experimental protocols to combine MB-FUS with cancer soluble biomarkers (ctDNA, proteins) to monitor targeted drug delivery in primary brain tumors, such as glioblastoma. We propose to first employ test molecules to study the secretion of ctDNA and associated proteins (GLuc) in small and large animal models and, subsequently, expand to ctDNA from oncogenes expressed in brain tumors. We will also employ mathematical modeling to guide our design, refine our protocols, investigate the impact of biological parameters, and extrapolate to humans. Overall, we expect that the proposed methods and technology will contribute to a more thorough understanding of biological barriers and responses to FUS treatment and create unique opportunities for safer and more effective diagnosis, treatment, and treatment monitoring of brain cancer.