Applications in the Clinic
Steve Anderson, Ph.D., will represent Labcorp (www.labcorp.com) and its subsidiary Viromed (www.viromed.com). One of the most famous success stories for a pharmacogenomic application in the clinic is the tale of Her2 and herceptin.
Her2 is a protein secreted by a subset of highly aggressive breast cancers. Genentech (www.genentech.com) developed a monoclonal antibody that binds to the receptors on the surface of the cells and results in the death of the cell. Labcorp was the primary testing laboratory that completed the studies necessary for Herceptin to be cleared as a cancer therapy.
“In a clinical trial, you could try to give the antibody to all women with metastatic breast cancer,” says Dr. Anderson. “You may or may not see a benefit because only a subset expresses that protein. What they decided to do was screen all potential individuals for levels of protein overexpression. This is a prime example of a targeted therapy where a diagnostic test is necessary to enrich the population.”
Additional studies on the Her2 gene showed that it was possible to do a genetic screen on the cancer cells. Multiple copies of Her2 on chromosome 17 were associated with aggressive cancers and a poorer prognosis.
Ginette Serrero, Ph.D., CEO of A&G Pharmaceuticals (www.agrx.net), has built her company around another breast cancer gene, GP88. She will be presenting at the IIR meeting the story of the development of a theranostic (biomarkers that have both therapeutic and diagnostic utility) that addresses the GP88 gene.
“In the case of GP88, I built up a cellular model system of tumorigenesis, starting from normal cells. From the normal cells, I developed cells that had increasingly higher tumorigenic properties. I compared these cells at the biological level and demonstrated that the tumorigenic cells were becoming dependent on their own conditioned culture medium to proliferate. If the cells become dependent on their own culture system, they are making what they need in contrast to the normal cells. From the culture medium of the tumorigenic cells, I purified and cloned GP88.”
According to Dr. Serrero, in fact, this approach, which worked with GP88, could work for the discovery of other cell surface biomarkers of cancer cells, a task that A&G is undertaking. “These proteins have the potential to be excellent diagnostic targets. Moreover, a diagnostic target can be converted to a therapeutic target by hooking up a toxin, for example.”
Oncology is one of the most common therapeutic areas for pharmacogenomics, but there are programs across a wide diversity of therapeutic areas. Gene Logic (www.genelogic.com) presented a case study of biomarkers discovered in patients with liver fibrosis and cirrhosis. The gene Fetuin-B was identified using in silico data mining with data from Affymetrix gene-expression arrays, and the results were presented at DDT.
The goal of the program was to find a biomarker that could be used in preclinical studies, and carry over into clinical studies. “At Gene Logic, we have built large genomic databases,” says Donna Mendrick, Ph.D., scientific fellow and vp of toxicogenomics. “Bioexpress® has 20,000 samples on Affymetrix arrays. The focus of Bioexpress is looking at normal and diseased human tissue. The second database is called the Toxexpress System, with over 14,000 samples. With it we are looking at control and toxicant compounds in rat tissues, primary hepatocytes, for example. That is where I started looking at toxic and treated rat tissues.”
These studies marry bioinformatics to pharmacogenomics, thereby leveraging two new technologies. “I am enthusiastic about this gene protein and this approach in general. When you have large databases, you can have large discoveries.”