Atsuo Sasaki, PhD, associate professor in the Division of Hematology Oncology within the UC College of Medicine and a member of both the UC Cancer and Gardner Neuroscience Institutes, has been awarded $448,208 from the National Institutes of Health to study a targeted and safe treatment for glioblastoma multiforme, the most aggressive form of brain cancer.
This award, an R21, is the third NIH grant at UC for Sasaki, who has been a faculty member and a member of the Brain Tumor Molecular Therapeutics Program since 2012. He has received roughly $2.2 million in federal grants since 2012.
In this study, Sasaki will examine how two compounds might impact glioblastoma multiforme and will work to develop a more potent compound to test on human cells and in animal models. The team of this project consists of prominent researchers from local (UC and Cincinnati Children’s Hospital Medical Center) and national institutions (NIH and the University of California, San Diego).
“The homeostasis of phosphoinositides—signaling lipids that have a huge impact on cell regulation—is critical for cellular health; imbalance of phosphoinositides could be harmful to rapidly growing cells,” he says. “Glioblastoma multiforme, which is the most aggressive brain tumor, elevates the phosphoinositide called PI(3,4,5)P3 to levels much higher than it naturally occurs, attributing to malignant growth. However, pharmacological targeting to reduce PI(3,4,5)P3 levels has shown limited success in clinical trials.
“In this study, we are proposing a reverse approach—a lethal combination of our identified compounds with the elevated PI(3,4,5)P3 in glioblastoma multiforme.”
In a preliminary study, researchers in Sasaki’s lab discovered two compounds—called GBM-Blast1 and GBM-Blast2—that “unbalanced” the phosphoinositides and led to catastrophic vacuolization (the formation of huge bubbles with membranes, like a balloon, inside cells) in the presence of PI(3,4,5)P3, eventually killing the brain tumor cells.
“Our biochemical analysis reveals that GBM-Blast1 and GBM-Blast2 possess a unique activity against phosphoinositide kinases, which regulate homeostasis of phosphoinositides,” Sasaki says. “Treatment of GBM-Blast1 and GBM-Blast2 with glioblastoma multiforme cells dramatically changed phosphoinositide balance.
“We found that this unique activity of GBM-Blast1 and GBM-Blast2 caused the vacuolization and cell death of glioblastoma multiforme cells. Importantly, GBM-Blast1 and GBM-Blast2 did not affect healthy cells.”
Sasaki says these findings reveal a potentially more targeted therapeutic treatment for this type of brain tumor and the other types of solid tumors that elevate levels of PI(3,4,5)P3.
“We’ll be doing further studies to define the anti-tumor effect of GBM-Blast1 and GBM-Blast2 on glioblastoma multiforme human cell lines and clinically relevant animal models, which could lead to targeted therapies for patients with this tumor and could potentially improve patient outcomes for a devastating illness.
“This study also has a potential to form a platform to target brain metastasized tumors because recent studies demonstrate that several types of brain metastasized tumors gain new genomic mutations that increase PI(3,4,5)P3 levels,” he says.