The goal of my research is to enhance our understanding of the genetic and molecular bases for inter-individual variability in chemotherapy response, with a focus on drug transporters and proteasomes.
I. Investigation of the impact of splicing variations on drug transporters and proteasomes
The production of distinct mRNA transcripts from a single gene via alternative splicing is a common, yet important mechanism of generating proteomic diversity in eukaryotic cells. While these splicing events are tightly regulated under normal physiological conditions, alterations in splicing patterns have been associated with disease development and variable response to drug therapy. Our research focus is to investigate the functional significance of splicing variants of genes involved in drug disposition (e.g. membrane transporters) or molecular targets for cancer therapy (e.g. proteasomes).
II. Immunoproteasome as a Novel Anticancer Target
The proteasome inhibitors have been actively pursued as novel anticancer agents. While bortezomib, a broadly acting proteasome inhibitor, has been approved for the treatment of multiple myeloma, the broad application of this drug is limited due to its side effects and development of resistance. In this regard, the approaches targeting the immunoproteasome, an inducible form of the proteasome, may provide an alternative strategy in cancer therapy. We are currently validating the immunoproteasome as a potential target for colorectal cancer treatment and the impact of genetic variations associated with the immunoproteasome subunits on the effectiveness of the immunoproteasome-targeting approach.
III. Cancer Pharmacogenomics
Interindividual differences in drug response and toxicities are consistently observed with most chemotherapeutic agents or regimens and many clinical variables (e.g., age, gender, diet, drug-drug interactions) affect drug responses. In particular, inherited variations in drug disposition (metabolism and transport) and drug target genes are known to substantially contribute to the observed variability in cancer treatment outcome. In our collaborative Phase II clinical study, we are investigating the clinical utility of pharmacogenomically selected treatment using genetic polymorphisms in patients with gastric and gastroesophageal junction (GEJ) cancer. In this study, we are analyzing DNA and tumor samples from the enrolled patients to identify possible confounding factors that may alter the expected outcomes of this treatment approach (e.g. other genetic variations, tumoral changes) and also assess the variability in the pharmacokinetics of anticancer agents as a potential cause for differing clinical outcome.