Lee:Research

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The overall goals of our research are i) to better understand the genetic and molecular bases for variable drug response and drug interactions with a focus on membrane transporters; ii) to develop novel anticancer drugs targeting the proteasomes and their delivery strategies to achieve desirable pharmacokinetic and pharmacodynamic profiles. 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. Alterations in splicing patterns have been increasingly associated with disease development and variable response to drug therapy. Our research focus is to investigate the functional significance and regulatory mechanisms of splicing variants of genes encoding membrane transporters or molecular targets for cancer therapy such as proteasomes. Our group was the first to report that colon and pancreatic cancer cells express the cancer-type variant of OATP1B3 (ct-OATP1B3) with the distinct mRNA and protein identity from the liver-type OATP1B3 detected in non-malignant hepatocytes (Thakkar et al. Mol Pharm 2013). We also identified hypoxia-inducible factor 1alpha (HIF-1alpha) as a positive regulator of ct-OATP1B3 expression (Han et al. Biochem Pharmacol 2013). Recently, we reported that the N-terminal region of OATP1B3 (which is present in liver-type OATP1B3, but not in ct-OATP1B3) plays a crucial role in regulating membrane trafficking of lt-OATP1B3 (Chun et al. Biochem Pharamcol 2017). We have also been investigating the impact of various genetic variations associated with different subunits that make up the multi-subunit protease complex called proteasomes. 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. 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. Thakkar N, Kim K, Jang ER, Han S, Kim K, Kim D, Merchant N, Lockhart AC, Lee W. A cancer-specific variant of the SLCO1B3 gene encodes a novel human organic anion transporting polypeptide 1B3 (OATP1B3) localized mainly in the cytoplasm of colon and pancreatic cancer cells. Mol Pharm. 2013;10(1):406-416. (PMID:23215050) Han S*, Kim K*, Thakkar N*, Kim D, Lee W. Role of Hypoxia Inducible Factor-1α in the Regulation of the Cancer-Specific Variant of Organic Anion Transporting Polypeptide 1B3 (OATP1B3) in Colon and Pancreatic Cancer. Biochem Pharmacol 2013;86:816-823 (*, equally contributed) (PMID: 23924606) Thakkar N, Lockhart AC, Lee W. Role of Organic Anion Transporting Polypeptides (OATPs) in Cancer Therapy, AAPS J. 17(3):535-45 (2015) (PMID: 25735612) Chun S-E, Thakkar N, Oh Y, Park JE, Han S, Ryoo G, Hahn H, Maeng SH, Lim Y-R, Han BW, Lee W The N-terminal region of Organic Anion Transporting Polypeptide 1B3 (OATP1B3) plays an essential role in regulating its plasma membrane trafficking. Biochem Pharmacol 131:98-105 (2017/05) (PMID: 28216016) Park JE, Ryoo G, Lee W. Alternative Splicing: Expanding Diversity in Major ABC and SLC Drug Transporters. AAPS J (accepted, 2017) II. Development of novel proteasome inhibitor drugs and delivery strategies to improve anticancer efficacy and expand therapeutic utilities The proteasome is an effective anticancer target, firmly validated by the FDA-approved drugs, bortezomib (Velcade®), carfilzomib (Kyprolis®) and ixazomib (Ninlalo®). These drugs have transformed the treatment landscape for multiple myeloma and other hematological malignancies. In particular, the second-generation proteasome inhibitor drug carfilzomib has become a mainstay in multiple myeloma therapy, with its much improved safety and efficacy profiles over bortezomib. Despite these remarkable successes, carfilzomib has shown limited efficacy in patients with solid cancers, possibly contributed by the poor in vivo stability and undesirable biodistribution profiles of the current carfilzomib formulation. Working together with experts in the field of drug delivery, we are currently investigating the potential of novel nano-formulations for carfilzomib in improving the anticancer efficacy in multiple myeloma and other types of cancers (Park et al. PLoS One, 2017). We also collaborate with the scientists who has the expertise and experience in the development of novel proteasome inhibitors. Our goal is to develop novel proteasome inhibitor drugs that can overcome the biopharmaceutical limitations orking together with our collaborators with 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.