H. Alex Brown, Ph.D., assistant professor of pharmacology and newly named Kimmel Foundation Scholar in the College of Veterinary Medicine at Cornell University, is assembling a research team to study the function of phospholipase D (PLD), a natural enzyme that is believed to be a crucial biochemical link in the cell-signaling cascade that permits the spread of many kinds of cancer cells.

The goal of Brown's research, which is supported in part by a two-year grant totaling $200,000 from the Sidney Kimmel Foundation for Cancer Research, is to understand the activation of PLD in cells and, ultimately, to design drugs that can inhibit PLD production in cancer cells and halt their spread altogether.

"If we can understand how PLD works, we will likely have explained one of the pathways for the division and migration of cancer cells," Brown said. "This enzyme seems to be associated with the proteins responsible for cell growth and cell cycles in many kinds of cancers. These are very complex chemical-signaling cascades. Some of these enzymes are like billiard balls: One hits another and sets off yet another cascade reaction. What we learn about the biochemistry and molecular structure of PLD and the other chemicals involved will almost certainly aid in the drug-discovery process, in rational drug design of new compounds."

At present there is no cancer drug that specifically targets PLD, and designing a drug to safely modulate the enzyme's activity will not be a simple task, Brown said, noting that every human body cell -- normal and otherwise -- is believed to utilize PLD. However, Brown says, the prospect of a a drug that would block tumor migration by interrupting cell-signaling is enough to warrant a long-term commitment on his part. He said he hopes to follow the PLD problem all the way from basic studies to drug design and will have expanded his four-person Cornell laboratory to nine investigators by this fall.

Brown already has made a good start on the PLD investigation, according to Geoffrey W.G. Sharp, Ph.D., D.Sc., professor and chair of pharmacology at the College of Veterinary Medicine. The young scientist succeeded where several others had failed in developing an assay for PLD activity, an achievement that Sharp says opened up a whole new area of investigation.

The PLD assay was developed while Brown was a postdoctoral researcher at the Southwestern Medical Center in Dallas, working with Paul Sternweis in a University of Texas department chaired by Alfred Gilman, recipient of the 1994 Nobel Prize in medicine for his groundbreaking work in signal transduction. Subsequently, Brown discovered that PLD is regulated by three proteins well known for their roles in cellular signal transduction or cancer: ADP-ribosylation factor, protein kinase C and CDC42.

"One of the reasons I wanted to develop my research in Cornell's Department of Pharmacology was to work closely with the laboratory of Rick Cerione, who did pioneering research in understanding the biochemistry of CDC42," Brown said. While completing his Ph.D. at University of North Carolina, Brown identified and characterized a previously unknown cell surface receptor. The P2U-puringenic receptor is now known to play an important regulatory role in most, and perhaps all, epithelial cells and many other cell types.

Brown joined the veterinary medical faculty in 1996. In addition to his research work, he will lecture on molecular and cellular medicine, signal transduction and oncology in both the DVM (doctor of veterinary medicine) and graduate curricula.