Victor Menezes

BioE Ph.D. Proposal Presentation

9:00 AM, Monday, May 6th, 2024

Location: UA Whitaker Building, Room 1214

Teams Meeting Link: https://tinyurl.com/2mdeabt2

Advisor:

Dr. Costas Arvanitis, Ph.D. (ME/BME, Georgia Institute of Technology & Emory)

Committee:

Dr. Levent Degertekin, Ph.D. (ME, Georgia Institute of Technology)

Dr. Gabe Kwong, Ph.D. (BME, Georgia Institute of Technology & Emory)

Dr. Philip Santangelo, Ph.D. (BME, Georgia Institute of Technology & Emory)

Dr. Ahmet Coskun, PhD. (BME, Georgia Institute of Technology & Emory)

Liquid Biopsy Combined with Focused Ultrasound for Brain Cancer Diagnosis and Response to Therapy Monitoring

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 also 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 fluid flow (transport) of macromolecules between the tumor core and the bloodstream. Although, in brain tumors the BBB is compromised (i.e., leakier), its permeability is highly heterogeneous and still restricts the transport of molecules.

Microbubble-enhanced focused ultrasound (MB-FUS) is a highly 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 (TME). Due to this ability this technology is currently under clinical evaluation for improving the delivery of anticancer agents in brain tumors. Hence, 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 for using MB-FUS in combination with cancer soluble biomarkers (ctDNA, proteins, etc.) to monitor targeted drug delivery (chemotherapy and immunotherapy) in primary brain tumors, such as glioblastoma. For our research we propose to, first, employ test molecules to study the secretion of ctDNA and associated proteins (Gaussia Luciferase) in small and large animal models and, subsequently, expand to ctDNA from oncogenes (KRAS and EGFRvIII) expressed in brain tumors. We will also employ mathematical modeling to guide our design, refine our protocols, investigate the impact of biological parameters (vascularity, porosity, secretion rate, cell death, etc.), and extrapolate to humans. Overall, we expect that the proposed methods, technology, and approach 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.