When he's not in the operating room performing surgery, Donald M. O'Rourke, M.D., Associate Professor of Neurosurgery at the University of Pennsylvania School of Medicine is fighting brain tumors from the research laboratory bench.
He and colleagues are making inroads to understanding the basic molecular biology that makes brain tumors so hard to treat. An estimated 41,000 new cases of primary brain tumors are expected to be diagnosed in 2004, according to the American Brain Tumor Association.
Most recently, O'Rourke and Gurpreet S. Kapoor, PhD, Research Associate in O'Rourke's laboratory, have discovered that two proteins sitting on the surface of cells are the interconnected switches for turning uncontrolled cell growth on or off in the brain and other tissues. These coupled proteins are the Epidermal Growth Factor Receptor (EGFR) and the Signal Regulatory Proteiná1 (SIRPá1). They report their findings in the September 15 issue of Cancer Research.
In past work, O'Rourke and colleagues found that if EGFR was activated, cancer cells tended to survive longer and migrate to unaffected parts of the brain to spread the cancer. In over 50 percent of glioblastomas – one type of brain cancer that is the leading cause of cancer-related deaths in males aged 20-39 – too much EGFR is produced. In other glioblastomas, too much of a variant called EGFRvIII is also produced, which is linked to poor survival and resistance to treatment in some brain-cancer patients.
"Most of my translational efforts are targeted at this variant form of EGFR since no treatments are out there for glioblastomas," says O'Rourke. "We believe that development of malignancy in the brain is not simply related to cell division; it's a combined process that involves cell division, cell survival, cell migration and movement, and ultimately angiogenesis – the building of new blood vessels in tumors." All four of these processes occur at the same time. Many of the conventional chemotherapies for brain tumors are directed at stopping cell division, which makes these therapies not completely successful.
Using human glioblastoma cells, they found that when another protein called SHP-2 is bound to EGFR, the cell goes into an overactive state, resulting in cancerous growth. However, when SHP-2 is bound to SIRPá1, uncontrolled cell growth is stopped. "This is probably the normal state for a brain cell," says O'Rourke.