New Treatments for Brain Cancer
Glioblastoma is the most aggressive and deadly form of brain cancer in adults. Even with surgery, radiation, and chemotherapy, most tumors return within a year, and fewer than one in ten patients survive five years after diagnosis. One of the main reasons glioblastoma is so difficult to treat is that the tumor is highly resistant to therapy and actively suppresses the body’s immune system, preventing it from fighting the cancer effectively.
It has been more than 20 years since a new therapy has been effective at extending this meager survival time in humans. Companion canines with glioma are becoming more readily acceptable as a translational model for human glioma, creating funding opportunities to study the canine disease and allowing for the possibilities of breakthroughs in treating canines and humans, alike.”
—Dr. Christine Toedebusch
Focusing on Immunological Response
A major focus of our research is on microglia—immune cells that normally protect the brain but are hijacked by glioblastoma tumors. These cells are extremely abundant within brain tumors and play a central role in helping the cancer grow, evade immune attack, and resist treatment. Tumor-influenced microglia shut down cancer-fighting immune cells, recruit other suppressive immune cells, and even help tumors survive radiation, chemotherapy, and experimental viral therapies. Rather than protecting the brain, these altered microglia create an environment that allows the tumor to thrive.
Importantly, microglia are found in all glioblastoma tumors, regardless of their genetic differences, making them an attractive target for new therapies. However, simply eliminating these cells has not worked in clinical trials, suggesting that microglia can play both helpful and harmful roles depending on context. Our work focuses on developing precise strategies to “reprogram” microglia—shifting them away from a tumor-supporting state and back toward an anti-tumor role. By targeting specific molecular switches that control microglial behavior, we aim to develop more effective and broadly applicable treatments for glioblastoma patients.
Developing Models to Study GBM Drug Delivery
Glioblastoma is an aggressive brain cancer with a devastating prognosis. Despite decades of research, treatment options have remained largely unchanged, and survival times have seen little improvement. One major reason is the blood-brain barrier (BBB) — a protective layer of cells that tightly controls what can enter the brain. While this barrier is essential for keeping the brain safe, it also blocks many potential therapies from reaching tumors. To develop better treatments, we first need better ways to study this barrier in the lab. Our model uses three types of brain cells — astrocytes, endothelial cells, and pericytes — that naturally come together to form tiny 3D structures called spheroids. These spheroids mimic key features of the blood-brain barrier, allowing us to test which drugs and therapies can successfully cross it. The images above show each cell type in a different color and illustrate what a fully formed spheroid looks like under the microscope. We are currently working to further validate this model and use it to screen promising new treatments for glioblastoma. This platform will enable rapid screening and assessment of nanoparticle uptake, trafficking, and BBB integrity in a human-relevant 3D system.
Collaborations in this space:
Dr. Orwa Aboud, MD PhD
University of California Davis
Dr. Orin Bloch, MD
University of California Davis
Dr. Randy Carney, PhD
University of California Davis
Dr. Felipe Godinez, PhD
University of California Davis
Dr. Yuanpei Li, PhD
University of California Davis
Dr. Cindy Lin, DVM PhD
University of California Davis
Dr. David Raleigh, MD PhD
University of California San Francisco
Dr. Luke Wittenburg, DVM PhD
University of California Davis
Dr. John Yu, MD
Cedars-Sinai
Support:
Comprehensive Cancer Center (NIH/NCI K12 CA138464)
NIH/NCI R01 CA253650 PI: John Yu
NIH/NCI R01 CA294557 PI: Yuanpei L