Overview

The research in my laboratory focuses on the pharmacogenomics of anti-neoplastic agents. Pharmacogenomics is the study of the role of inheritance in variation in drug response, either efficacy or toxicity. Most anti-neoplastic drugs have narrow therapeutic indices.  Therefore, treatment with these drugs can result in significant, sometimes, life-threatening drug-induced toxicity. At the same time, the therapeutic response to those agents is variable. For example, the proteasome inhibitors used to treat refractory multiple myeloma only achieve 30-35% response rates, which is already a great success when compared with “conventional” therapy. It is important to predict which sub-populations will respond in order to achieve better therapeutic effect and to avoid toxicity. That is the goal of pharmacogenomics and the future of medicine—individualized therapy.

The PI for this research program has been involved in research on the pharmacogenomics of drug metabolizing enzymes for anti-neoplastic drugs such as the thiopurines, which are widely used to treat childhood acute lymphoblastic leukemia (ALL). One of the enzyme metabolizing these drugs is called thiopurine S-methyltransferase (TPMT). This enzyme is genetically regulated, and one out of 300 individuals in Caucasian populations is homozygous for the most common variant allele (*3A), containing two nonsynonymous cSNPs (single nucleotide polymorphisms resulting in alteration of the encoded amino acid). When treated with standard dose of thiopurine drugs, these patients will have life-threatening drug-induced toxicity—bone marrow suppression. Therefore, these patients have to be treated with 1/10th to 1/15th of the standard dose. The mechanism responsible for this clinically significant phenomenon is that the two nonsynonymous cSNPs cause the protein to misfold, and the misfolded protein is then recognized by the cellular degradation machinery, either through proteasome-mediated degradation or it can form aggresomes in the cell. This is the first example, a striking pharmacogenomic example, having both significant clinical implications and also serving as a model system for understanding functional genomic mechanisms in vitro. This pharmacogenomic research program will move beyond just focusing on drug metabolism, to focusing on drug effects, including “drug targets” and downstream signaling from these targets. One example being studied is proteasome inhibitors. We have already identified genetic variation in the targets for these drugs--proteasome subunits--and will now use this information to understand the role and the underlying mechanisms responsible for individual variation in drug response and, eventually, translate that information to the clinic to better select patients and to avoid severe toxicity.

Pharmacogenomics is a rapidly growing field, and it has already had real impact on the practice of medicine. Our laboratory is actively involved in the pharmacogenomics of the treatment of anti-neoplastic agents. The focus will be to identify and understand the role of genetic variation in the response to drug therapy, either efficacy or toxicity, and—eventually—to translate that knowledge to the clinic. Therefore, two major activities will be ongoing in the laboratory. One is to understand the functional and mechanistic effects of that genetic variation and the other is to serve as a “bridge” from the bench to the bedside through involvement in clinical translational pharmacogenomic studies.