Dao M. Nguyen, M.D.
Associate Professor of Surgery
Description of Research
The focus of Dr. Nguyen’s translational research program is to target receptor-mediated signal transduction of cancer cells to achieve anti-tumor effects. This is achieved either by 1) direct activation of the death receptors (Fas or TRAIL R1/2) using recombinant apoptosis-inducing ligands MegaFasL or Apo2L/TRAIL; or 2) by inhibition of growth factor receptors EGFR or EGFR-dependent intracellular signal transduction pathways using selective pharmacologic kinase inhibitors.
While expressing adequate levels of functional death receptors DR1 and DR2, the majority of thoracic cancer cells (non-small cell lung cancer, esophageal cancer or malignant pleural mesothelioma) are refractory to the recombinant soluble Apo2L/TRAIL. Treating these Apo2L/TRAIL-refractory cells with sublethal doses of cytotoxic chemotherapeutic agents significantly sensitizes them to Apo2L/TRAIL. We have further demonstrated the mitochondria-dependent caspase activation feedback loop is essential for this chemotherapy-mediated Apo2L/TRAIL sensitization. This finding leads to focused efforts in designing a therapeutic strategy that directly and selectively targets and activates the mitochondria to induce sensitization of cancer cells to the second death signal delivered by APo2L/TRAIL. Moreover, Dr. Nguyen’s lab also has been exploring the therapeutic application of tumor-selective adenovirus expressing membrane-bound TRAIL under the transcription control of the hTERT promoter. This TRAIL gene therapy is particularly applicable for a disease condition such as esophageal cancer in which the tumor can be accessed by endoscopy for direct intratumoral injection of virus. The focus of our laboratory investigation at University of Miami/Sylvester Comprehensive Cancer Center (UM), in collaboration with Dr. Niramol Savaraj (research professor at UM and medical oncologist at the Miami VA Medical Center), in the last 18 months has been on elucidating the molecular mechanism of the supra-additive anticancer property of the combination of Apo2L/TRAIL and the histone deactylase inhibitor SAHA or the arginine-depleting agent ADI in malignant pleural mesothelioma (MPM). We have observed that SAHA differentially mediates reduction of XIAP level in MPM cells that are susceptible to SAHA+Apo2L/TRAIL and not in those that are refractory to this drug combination. Selective XIAP knockdown using siRNA sensitizes MPM cells to Apo2L/TRAIL. Moreover, direct targeting of XIAP using pharmacologic inhibitor (also known as SMAC-mimetic) also potentiates MPM cells to Apo2L/TRAIL cytotoxicity. These observations form the basis of our future investigation that focuses on the development of targeted molecular therapy for MPM as well as other thoracic cancers using Apo2L/TRAIL and XIAP inhibitor.
Another project that has been carried out in the laboratory as a continuation of previous works is the evaluation of MEK inhibitors as antiangiogenic agents. Pharmacologic abrogation of MEK signaling mediates inhibition of cell proliferation but not apoptosis of cultured malignant cells. On the other hand, MEK inhibitor significantly induces apoptosis of primary human umbilical endothelial cells (HUVEC). More importantly, MEK inhibitor also significantly suppresses the production of pro-angiogenic cytokines (VEGF, IL-8, prostaglandin E2) by culture cancer cells in vitro at drug concentrations many folds lower than those that mediate cell growth inhibition. Parenteral administration of the prototypic MEK inhibitor UO126 to nude mice bearing the MPM H513 subcutaneous tumor xenografts caused dose-dependent reduction of tumor growth that was associated with drug target effects of reduction of MEK signaling (abrogation of pERK), reduction of expression of proliferating marker Ki67 and capillary density that was coupled with increased apoptosis of tumor tissue as detected by increased active caspase 3 expr
Highlights
- Identification of the essential role of the mitochondria and the intrinsic caspase cascade in mediating chemotherapy-induced sensitization of cancer cells to Apo2L/TRAIL
- Identification of the profound apoptogenic activity of the combination of histone deacetylase inhibitor depsipeptide and the kinase inhibitor flavopiridol
- Targeting the NF-kB pathway using the inhibitor Parthenolide or the PKC inhibitor to sensitize cancer cells to the cytotoxic effect of histone deacetylase inhibitor Trichostatin A or depsipeptide
Selected Cancer-Related Publications
- Cheung MC, Hamilton K, Sherman R, Byrne MM, Nguyen DM, Franceschi D, Koniaris LG. Impact of Teaching Facility Status and High-Volume Centers on Outcomes for Lung Cancer Resection: An Examination of 13,469 Surgical Patients. Ann Surg Oncol 16:3-13, 2009. Read more »
Programs
Collaborating in the Multidisciplinary Research Program(s):