I. Roles of Drug Transporters in Cancer Therapy
The goal of our research is to understand the genetic and molecular bases for interindividual variations with a particular emphasis on drug transport. We are currently investigating the function and regulation of drug transporters in cancer development and progression. Our laboratory recently reported that OATP1B3, a member of OATP transporter family, is highly upregulated in colon cancer and we are examining the functional implications of OATP1B3 in cancer therapy as well as the regulatory mechanisms underlying its overexpression in cancers. In another project, we are also assessing the role of the efflux and uptake transporters in developing acquired resistance to chemotherapeutic agents.
II. 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.
III. 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.