My pharmacogenomic laboratory will focus on the genetic variation in genes encoding proteins involved in metabolism, transport and mechanisms of action of anti-neoplastic agents. Specifically, we are interested in the pharmacogenomics of proteasome inhibitors, such as bortazomib that has been approved by the FDA to treat refractory multiple myeloma and also is being tested for various solid tumors. However, the response to bortezomib is only about 30%. Multiple factors might influence that response rate and genetic variation in the targets for proteasome inhibitors might be one major factor. By resequencing genes encoding three proteasome subunits which are the targets for the proteasome inhibitors, we have already identified common genetic polymorphisms within the genes encoding these subunits. The next step will involve functional characterization of the effects of these polymorphisms, both in vitro and in vivo, by using a variety of cell biology and genomic techniques. The ultimate goal of pharmacogenomics is to translate information from the bench to the bedside. We are collaborating with the multiple myeloma group at the Mayo Clinic and will translate information into the clinic to determine whether these genetic variations might have effects in response to the treatment of the proteasome inhibitors . The other project will involve applying similar concepts and techniques to study the pharmacogenomics of dexomethasone, another widely used anti-cancer drug, both from a pharmacodynamic prospective, such as the glucocortocoid receptor and down stream signaling and also pharmacokinetic propective, such as 11beta-HSD which converts between inactive and active forms in vivo.
These are representative projects ongoing in my laboratory. The projects are interesting and challenging because of the abundant genomic information available. The important question is how to scientifically determine the function of common genetic polymorphisms and apply these data to achieve truely individualized medicine. My laboratory is trying to contribute to this area of biomedical research.