Daekyu Sun, PhD
My research activities are directed toward discovering new agents that are more selective for cancer cells than normal cells with novel mechanisms of action, elucidating the mechanisms of action of novel natural products with antineoplastic activity, and understanding drug resistance mechanisms in human cancer cells to anticancer drugs. My laboratory's research projects focus on three specific areas, as described below.
1. Suppression of mutated RET expression in MTC with small molecules
Medullary thyroid carcinoma (MTC) represents the most frequent initial diagnosis for multiple endocrine neoplasia type 2 (MEN2) and is the most common cause of death in these syndromes. Activating germline RET mutations are known to play a central role in the development of MEN2 syndromes. Therefore, the RET protooncogene has been proposed to have a significant place in the prevention and treatment of cancers caused by these syndromes. Not surprisingly, recently developed molecular therapeutics that target the RET pathway have shown activity in clinical trials of patients with advanced MTC, a disease for which there has been no effective therapy. Our early work has shown that G-rich and C-rich strands could form specific G-quadruplex or i-motif structures, respectively, on the polypurine/polypyrimidine tract in the proximal promoter of the human RET gene. That observation led us to explore a new therapeutic strategy to blunt the effect of mutations in RET associated with MTC using small molecules (anti-RET agents) that specifically inhibit the transcriptional activation of this gene. Ultimately, we hope to directly evaluate the antitumor effects of anti-RET agents in a preclinical model of human MTC, a tumor type characterized by germline point mutations of the RET proto-oncogene.
2) Targeting Tumor angiogenesis by targeting the transcriptional activation of the VEGF gene
It is widely believed that angiogenesis, the formation of new blood vessels, promotes tumor growth by providing oxygen and nutrients to proliferating cancerous cells. The switch to an angiogenic phenotype in cancer cells is often mediated by increased expression of vascular endothelial growth factor (VEGF), which is a pluripotent cytokinine and angiogenic growth factor and is often transcriptionally activated by the transcription factor HIF-1a under hypoxic condition. Our early work has shown that the G-rich and C-rich strands could form specific G-quadruplex or i-motif structures, respectively, on the polypurine/polypyrimidine tract in the proximal promoter of these genes. That observation led us to explore a new therapeutic strategy to repress transcriptional activation of human VEGF gene with small molecules capable of binding selectively to non-canonical DNA structures formed within the promoter region of these genes. The results from our research are anticipated to lead to the discovery of novel anti-angiogenic compounds that we could find important applications in the treatment of human cancers.
3) Targeting inducible chemotherapy resistance mechanisms in human cancer
Other aspects of our research focus on understanding inducible resistant mechanisms in human cancer cells to DNA-damaging anticancer drugs, since the acquisition of chemoresistance toward chemotherapy in cancer cells remains one of the principal obstacles to the effective treatment of malignancies. Recently, by combining global transcriptional profiling and bioinformatics, we have deciphered large networked responses to damage caused by the anticancer drug gemcitabine as a model compound in human cancer cells. This large-scale approach particularly contributed to the identification of numerous gene products potentially associated with chemoresistance to anticancer drugs in cancer cells. The functional roles of these genes in the induction of chemoresistance against these anticancer drugs in human cancer cells will be characterized by further functional analysis. Identified genes with a suspected DNA repair function from our proposed study will be of potential importance in uncovering drug resistance mechanisms of cancer cells and in identifying a potential target for therapeutic intervention.
BPharm, Sung Kyun Kwan University, Seoul, 1984, Pharmacy
MS, Korean Advanced Institute of Science and Technology, Seoul, 1986, Biological Science and Engineering
PhD, University of Texas at Austin, 1992, Pharmacy/Medicinal Chemistry
Shin YJ, Kumarasamy V, Camacho D, Sun D. Involvement of G-quadruplex structures in regulation of human RET gene expression by small molecules in human medullary thyroid carcinoma TT cells. Oncogene 2014 Mar 24 [Epub ahead of print].
Kumarasamy VM, Sun D (2013) Current and Future Views in G-Quadruplex Secondary Structure as an Anti-Cancer Target. J Phys Chem Biophys 3: e117 (2013).
Uribe DJ, Shin YJ, Lau E, Ebbinghaus SW, Sun D. Heterogeneous nuclear ribonucleoprotein K binds to the cytosine-rich sequence of the hypoxia inducible factor 1 alpha proximal promoter that forms a stable i-motif at neutral pH. J Phys Chem Biophys S5: 001 (2013).
Keerthi K, Rajapakse A, Sun D, Gates KS. Synthesis and characterization of a small analogue of the anticancer natural product leinamycin. Bioorg Med Chem 21(1):235-41 (2013).
Viswesh V, Hays AM, Gates K, Sun D. DNA cleavage induced by antitumor antibiotic leinamycin and its biological consequences. Bioorg Med Chem 20:4413-21 (2012).
Sivaramakrishnan S, Breydo L, Sun D, Gates KS. The macrocycle of leinamycin imparts hydrolytic stability to the thiol-sensing 1,2-dithiolan-3-one 1-oxide unit of the natural product. Bioorg Med Chem Lett 22:3791-4 (2012).
Sinha P, Shin Y, Hays AM, Gates K, Sun D. Cellular responses to the DNA damaging natural compound leinamycin. J Cancer Sci Ther S8:003 (2012).
Sun D, Guo K, Shin YJ. Evidence of the formation of G-quadruplex structures in the promoter region of the human vascular endothelial growth factor gene. Nucleic Acids Res 39:1256-65 (2011).
Uribe DJ, Guo K, Shin YJ, Sun D. Heterogeneous nuclear ribonucleoprotein K and nucleolin as transcriptional activators of the vascular endothelial growth factor promoter through interaction with secondary DNA structures. Biochemistry 50:3796-806 (2011).
Viswesh V, Gates K, Sun D. Characterization of DNA damage induced by a natural product antitumor antibiotic leinamycin in human cancer cells. Chem Res Toxicol 23(1):99-107 (2010).
Sun D, Hurley LH. Biochemical techniques for the characterization of G-quadruplex structures: EMSA, DMS footprinting, and DNA polymerase stop assay. Methods Mol Biol 608:65-79 (2010).
Sun D. In vitro footprinting of promoter regions within supercoiled plasmid DNA. Methods Mol Biol 613:223-33 (2010).
Sun D, Melman G, LeTourneau NJ, Hays AM, Melman M.. Synthesis and antiproliferating activity of the iron chelators of the hydroxyamino-1, 3, 5-triazine family. Bioorg Med Chem Lett 20:2458-460 (2010).
Zheng J, Liu X, Yuan Q, Shin YJ, Sun D, Lu Y. Thiol-dependent DNA cleavage by aminomethylated Beaucage’s reagent. Org Biomol Chem 8:1293-5 (2010).
Guo K, Gokhale V, Hurley LH, Sun D. Intramolecularly folded G-quadruplex and i-motif structures in the proximal promoter of the vascular endothelial growth factor gene. Nucleic Acids Res 36:4598-608 (2008).
Sun D, Liu WJ, Guo K, Rusche JJ, Ebbinghaus S, Gokhale V, Hurley LH. The proximal promoter region of the human vascular endothelial growth factor gene has a G-quadruplex structure that can be targeted by G-quadruplex-interactive agents. Mol Cancer Ther 7:880-9 (2008).
Guo K, Pourpak A, Beetz-Rogers K, Gokhale V, Sun D, Hurley LH. Formation of pseudosymmetrical G-quadruplex and i-motif structures in the proximal promoter region of the RET oncogene. J Am Chem Soc 129:10220-8 (2007).
Dexheimer TS, Sun D, Hurley LH. Deconvoluting the structural and drug-recognition complexity of the G-quadruplex-forming region upstream of the bcl-2 P1 promoter. J Am Chem Soc 128:5404-15 (2006).