Daekyu Sun

Sun's 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.  His 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 cytokine 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.