The goal of our research is to better understand 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 and other genetic 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).
Our group was the first to report the distinct mRNA and protein identity of cancer-specific splicing variants of OATP1B3 expressed in colon and pancreatic cancer (Thakkar et al. Mol Pharm 2013) and to identify hypoxia-inducible factor 1alpha(HIF-1alpha) as a positive regulator of csOATP1B3 V expression (Han et al. Biochem Pharmacol 2013). We are currently investigating the mechanisms underlying the defective membrane trafficking of cancer-specific OATP1B3 variant.
We are also investigating the impact of various genetic variations associated with the proteasome subunits. The β1i subunit of the immunoproteasome harbors frequently occurring genetic variations (p.60R>H) and conflicting results had been reported with regard to its functional impact on the immunoproteasome activity. Recently, we reported that the codon 60 genetic variations of the β1i subunit do not account for variable expression/activity of the immunoproteasome (Park et al. PLoS One 2013). Currently we are investigating the impact of alternatively spliced transcripts of the proteasome subunits on the proteasome function.
II. Immunoproteasome as a Novel Anticancer Target
The proteasome is an effective anticancer target, firmly validated by the FDA-approved drugs, bortezomib (Velcade®) and carfilzomib (Kyprolis®). Despite their remarkable successes in treating hematological malignancies, these drugs often cause severe side effects, likely arising from the inhibition of the constitutive proteasome present in all cell types. As a strategy to overcome these limitations of the existing proteasome inhibitor drugs, we hypothesized that selective targeting of the immunoproteasome upregulated in cancer cells may provide an alternative strategy to achieve anticancer efficacy and reduce unwanted side effects. In collaboration with the laboratory of Dr. Kyung Bo Kim (UK, College of Pharmacy), we are currently investigating the biological impact of the immunoproteasome inhibition and therapeutic potential of novel immunoproteasome-selective inhibitors.
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.