Blocking YAP May Aid in Treating Brain Cancer
A few years ago, a team of brain cancer researchers ventured a hypothesis. The team wondered whether a particular protein, known as Yes-Associated Protein, or YAP, which is involved in human development and present in the brain, might also drive the aggressiveness of brain tumors.
“As we were getting started, I was completely skeptical that the pathway involving YAP had any relevance to cancer,” says Alfredo Quinones-Hinojosa, M.D., chair of Neurosurgery on Mayo Clinic’s Florida campus. As their research progressed, the team found YAP prompts glioblastoma cells to invade surrounding brain tissue.
The team has taken the next step, with the goal of bringing hope to patients. In the American Chemical Society’s publication Molecular Pharmaceutics, they report a drug, verteporfin, known to inhibit YAP is capable of reducing the growth of highly aggressive glioblastoma cells in animal and cell models. They also report that the drug makes glioblastoma cells more susceptible to radiation.
With collaborators at Johns Hopkins, the team developed a method to encapsulate verteporfin in a slowly degrading microparticle.
“The idea would be to leave the encapsulated drug in the cavity where a brain tumor has been surgically removed. The microparticle would enable the drug to release slowly over time to reduce tumor recurrence,” explains Dr. Quinones-Hinojosa, the study’s principal investigator.
“Our results suggest the drug will work on other non-central nervous system tumors, including chordomas and meningiomas,” says lead author Sagar Shah, Ph.D., who was a post-doctoral fellow at Mayo Clinic and is now at Cornell University.
The next steps will be to test the drug in mouse models of glioblastoma. Working with Mayo Clinic’s Center for Regenerative Medicine, the team also is determining methods to scale up good manufacturing practices of the microparticle.
It turns out YAP functions by affecting the mechanics of cell movement. In Nature Communications, Dr. Quinones-Hinojosa and Dr. Shah were leading members of a team that found YAP is part of a cue-driven process that leads cancer cells to metastasize. In both normal and cancerous tissue, cells are joined in sheets that communicate and function together like an army unit, coordinated together at the rear, while sending reconnaissance units from a front edge. YAP orchestrates the coordination at the rear, but, responding to mechanical and chemical cues in the tumor environment, also prompts cells from the front edge to disperse, leading to metastases. The team found this process, dictated by YAP, central to the invasiveness of renal cancer.
But YAP’s mechanical workings, both in cell movement and in shape-changing, are not only relevant to tumors. Dr. Quinones-Hinojosa and Dr. Shah were also part of a team that reported in Nature Biomedical Engineering that YAP’s role in cell mechanics is also a driving force in asthma.
In the case of an asthma attack, the smooth muscle of the airways contracts. YAP is involved in a feedback loop that engages mechanical and biochemical stresses in epithelial cells involved in constriction. The findings suggest a new mechanic-chemical mechanism for asthma and a new target for therapies.
“This is a protein that’s involved in normal developmental pathways, but its mechanism is hijacked by other pathophysiological phenomena,” says Dr. Quinones-Hinojosa. “These studies enable us to think about new ways to stop those processes.”
In addition to Dr. Quinones and Dr. Shah, the research team that published in Molecular Pharmaceutics includes: Paula Schiapparelli, Ph.D., and Carla A. Vazquez-Ramos, of Mayo Clinic; as well as Jayoung Kim, Ph.D., Juan C. Martinez-Gutierrez, M.D., Alejandro Ruiz-Valls, M.D., Kyle Inman, James G. Shamul, and Jordan J. Green, Ph.D., of Johns Hopkins.