What do you get when you add 1 innovative researcher, 4 creative projects, and 5 top-notch collaborators? 5 grants in 1 month!
Susann Brady-Kalnay, PhD, is on a roll. Brady-Kalnay, a professor of molecular biology and microbiology in the School of Medicine, received five grant awards this past July to support her research on cell adhesion molecules in the spreading of cancer.
“I’ve been a researcher in the lab for thirty years and a professor at Case Western Reserve for 22 years,” she said, “and this is the first time so many awards came in a single month. I’m very grateful to the funders.”
Cell adhesion molecules are proteins located on the outer surface of cells that help the cells fasten to each other and their surroundings. “Because of cell adhesion molecules, cells are able to form organs and other components of the body,” said Brady-Kalnay. “Unfortunately, alterations in these molecules also play a major role in cancer growth, invasion, and metastases.”
Previously, Brady-Kalnay found that in glioblastoma multiforme (GBM), the most deadly form of brain cancer, a cell adhesion molecule called PTPmu is cut into fragments by the cancer cells, a process known as proteolysis. “Shutting down the inhibition of cellular motion in this way enables the cancer cells to migrate to other areas of the body,” she said.
This is a crucial discovery because GBM cells are notorious for their ability to spread throughout the brain, making it difficult to surgically remove all of the cancer. Brady-Kalnay found that adding unbroken PTPmu protein to cancer cells reduced their ability to migrate. She then designed a very small protein – the SBK2 peptide – which recognizes one of these tumor-specific PTPmu fragments. Specifically, the peptide becomes a tumor imaging agent when coupled to a fluorescent dye that makes it glow red under a certain wavelength of light, enabling surgeons to spot and remove cancer cells that have migrated away from the tumor.
Two of the five grant awards she received this past summer grants will support clinical development of the PTPmu tumor imaging agent. An NIH Academic Industrial Partnership grant and a Case Coulter Translational Research Partnership grant will enable Brady-Kalnay and Andrew Sloan, MD, neurosurgery professor, to develop the agent for clinical use. “Now we can detect cancer in our models with the PTPmu molecular imaging agent. Its clinical development will allow surgeons to see where tumors are and cut them out with higher levels of precision,” she said. “For all of the cancer that can’t be surgically removed, we can use the same SBK2 peptide as a targeting agent to deliver anti-cancer drugs directly to the tumor cells. This allows us to increase the dosage without the side effect of harming nearby normal cells.” The industrial partner in this research project is Core Clinical Inc. and its CEO, Ted Gastineau.
Next, an award from Alex’s Lemonade Stand Foundation will enable Brady-Kalnay and Stathis Karathanasis, PhD, associate professor of biomedical engineering and radiology, to develop PTPmu-based nanoparticles to attack pediatric brain tumor cells and release their drugs by vibrating at an appropriate radiofrequency.
An award from the Mary Kay Foundation will allow Brady-Kalnay and two colleagues, Agata Exner, PhD, professor of radiology and biomedical engineering, and Analisa DiFeo, PhD, assistant professor of general medical science-oncology, to combine standard ultrasound equipment with the PTPmu targeting agent, coupled to a therapeutic ultrasound-visible nanoparticle, to more accurately detect and kill ovarian cancer cells while reducing side effects associated with administering untargeted chemotherapeutics.
Under the fifth grant, Brady-Kalnay is one of the first researchers to receive the inaugural Atomwise Inc. Artificial Intelligence Molecular Screen (AIMS) award. It will allow her to develop medicinal compounds that inhibit the PTPmu enzyme to treat glioblastoma. “The four other grants focus on the adhesion capacities of PTPmu,” she said. “This one focuses on the internal part of the cell, with an aim of developing a medication to block the migration and invasion of the tumor cells.”
Combined, the five awards represent a way for refining and expanding an overall framework that Brady-Kalnay has been developing for decades. “Seeing it all come together like this is truly a gratifying – and humbling – experience,” she said.