David Plas, PhD, Associate Professor of Cancer Biology at the University of Cincinnati College of Medicine, brings a fresh viewpoint and the mindset of a leukemia researcher to the problem of glioma, a stubbornly aggressive form of brain cancer. He notes that while leukemias are treated more successfully than ever before, “gliomas could stand some major improvements.”

Dr. Plas is among a cadre of researchers at the UC Cancer Institute whose expertise is being tapped by the UC Brain Tumor Center, which straddles both the Cancer Institute and the UC Neuroscience Institute. Together these talented researchers are homing in on the molecular profile of glioma, a cancer that develops from glial cells in the brain and whose most common form is glioblastoma multiforme.  An estimated 13,000 Americans die of brain and other nervous system cancers each year.

“In order to bring personalized therapy to brain cancers, it is necessary to develop new drugs that target the major pathways used by cancer genes,” Dr. Plas says. “Unfortunately, this approach has not yet been successful in brain cancer. We hope to bring some of the ideas from the world of leukemia research into brain cancer and see whether they can be successfully applied or modified.”

Armed with a $100,000 pilot grant funded locally and awarded by the UC Brain Tumor Center’s Molecular Therapeutics Program, a translational research program that leads to Phase I clinical trials, Dr. Plas and his laboratory team are focused on a protein known as S6Kinase1, or S6K1. The protein is in a pathway downstream of another protein, PTEN, a major tumor suppressor that is frequently mutated in glioma. The deficiency of PTEN occurs in all four molecular subtypes of glioblastoma.

Dr. Plas and his laboratory team have assembled a panel of five pre-clinical compounds through collaboration with chemists from the pharmaceutical industry as well as leading academic chemists. Using these compounds, they are performing the first comprehensive analysis of S6K1 as a target for brain cancer therapy.

“This work will provide the critical first step for a new direction in the development of new drugs for personalized cancer therapy of brain cancer,” Dr. Plas says.

Dr. Plas notes that S6K1 is a type of kinase – a protein that modifies other proteins – that has not yet been targeted. “We’ve only recently become able to target S6K1,” he says. “We are hoping to be on the front wave of targeting this pathway toward the development of S6K1 inhibitors.”

Work in the Plas Lab fits into a larger picture of innovative laboratories at UC that are developing molecule-targeted therapies for glioblastoma. The laboratories of El Mustapha Bahassi, PhD, and James Driscoll, MD, PhD, for example, are focusing on mutations on the epidermal growth factor receptor (EGFR). In glioblastoma, EGFR can lead to faulty signaling or “overactivation,” which causes cells to multiply too rapidly and to result in cancer. At least 30 to 50 percent of glioblastoma cases involve a malfunction of the EGF receptor. Dr. Plas notes that, “EGFR actually controls many different pathways. One of those pathways leads to S6Kinase1. So you can say that our work is related because these pathways are often interconnected.”

Dr. Plas says that one can visualize cancer from a genomic view (according to chromosomes or genes) or from a pathway view (according to molecular interactions). Metaphorically, one might imagine the chromosomes as busy airports and the pathways as the flights that go between them.

Dr. Plas is clearly excited about the developments. “We have an opportunity to use targeted therapeutics that have not been successfully applied in glioma therapy,” he says. “What draws our interest is the importance of the problem.”

 

— Cindy Starr