Dao M. Nguyen, M.D.
Associate Professor of Surgery
Description of Research
The focus of Dr. Nguyen’s translational research program is to develop clinically applicable targeted molecular therapies to treat primary thoracic neoplasms such as non-small cell lung cancer (NSCLC) or malignant pleural mesothelioma (MPM). The strategies employed are to target the hedgehog (HH) signal transduction pathway in these thoracic cancers using novel pharmacolgic inhibitors or repurposing old pharmaceuticals that are FDA-approved for other clinical indication but recently shown to have anti-HH activity. Hedgehog-mediated signaling network is active during embryonic development and essential for organgenesis but quiescence in differentiated mature tissues only to be reactivated during tissue injury/repair. It, together with Wnt and Notch pathways, plays important role in the function of stem cells, including cancer stem cells. More recently, HH signal transduction pathway has been shown to be re-activated in many epithelial cancers including primary cancer of the lung and the pleura and in many neoplams such as basal cell carcinoma or medulloblastoma that HH pathway is the oncogenic driver of tumor maintenance and progression. Selective targeting HH pathway using pharmacologic inhibitor of SMO, the receptor-activator of HH pathway, GDC-0449 leads to significant tumor response. Whether attenuation of HH-mediated signaling by pharmacologic pathway inhibitors would also result in growth suppression of NSCLC or MPM remains to be demonstrated. Our laboratory is also interested in developing strategy to potentiate the therapeutic efficacy of the FDA-approved SMO antagonist GDC-0449 by inhibiting the treatment-induced autophagic response or by attenuating SMO-independent activation of Gli in NSCLC or MPM. Another line of research being investigated in our laboratory is to induce nutritional stress in NSCLC cells lacking the expression of the enzyme ASS by depleting arginine in the culture medium using the clinical grade arginine-degrading enzyme ADI-PEG20. Tumor cells without ASS expression cannot synthesize arginine from its precursor and thus totally dependent on external source of arginine, a semi-essential amino acid, for survival. Normal tissues always express ASS and thus not susceptible to ADI-induced arginine depletion. NSCLC cells can be phenotypically stratified based on levels of ASS expression by immunohistochemical staining for ASS (pathologic tumor tissues) or by western blots for ASS proteins/RT-PCR for mRNA of ASS1 transcripts. Tumor cells with low or no expression of ASS will be treated with ADI-PEG20. Research also focuses on development of strategies to circumvent the problems related to emergence of ADI-PEG resistance secondary to re-expression of ASS or induction of the cytoprotective autophagic response. This truly represents individualized targeted molecular therapy on the basis of baseline expression of ASS in tumor tissues.
- Demonstration that HH signaling is active in MPM and repurposing Itraconazole (an anti-fungal drug with SMO antagonistic activity) or arsenic tri-oxide (an anti-leukemic drug recently shown to have Gli inhibitory activity) to treat MPM in preclinical studies.
- Demonstration that GDC-0449, a FDA-approved SMO inhibitor, accentuates autophagy in NSCLC and MPM cells and abrogation of which by chloroquine, an anti-malaria, anti-arthritic drug that is being evaluated as anti-autophagy drug currently in phase I/II clinical trials, results in supra-additive anticancer activity in vitro.
Selected Cancer-Related Publications
- Xin HW, Yang JH, Nguyen DM. Sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor requires e-cadherin in esophageal cancer and malignant pleural mesothelioma. Anticancer Res 33:2401-8,2013 Read more »
- You M, Varona-Santos J, Singh S, Robbins DJ, Savaraj N, Nguyen DM. Targeting of the Hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro. J Thorac Cardiovasc Surg :,2013 Read more »
- Saeed AM, Toonkel R, Glassberg MK, Nguyen D, Hu JJ, Zimmers TA, Robbins DJ, Koniaris LG, Lally BE. The influence of Hispanic ethnicity on nonsmall cell lung cancer histology and patient survival: An analysis of the Survival,Epidemiology,and End Results database. Cancer :,2012 Read more »
- Rodriguez-Blanco J, Schilling NS, Tokhunts R, Giambelli C, Long J, Liang Fei D, Singh S, Black KE, Wang Z, Galimberti F, Bejarano PA, Elliot S, Glassberg MK, Nguyen DM, Lockwood WW, Lam WL, Dmitrovsky E, Capobianco AJ, Robbins DJ. The Hedgehog processing pathway is required for NSCLC growth and survival. Oncogene :,2012 Read more »
- You M, Savaraj N, Kuo MT, Wangpaichitr M, Varona-Santos J, Wu C, Nguyen DM, Feun L. TRAIL induces autophagic protein cleavage through caspase activation in melanoma cell lines under arginine deprivation. Mol Cell Biochem :,2012 Read more »
- Klapper JA, Davis JL, Ripley RT, Smith FO, Nguyen DM, Kwong KF, Mercedes L, Kemp CD, Mathur A, White DE, Dudley ME, Wunderlich JR, Rosenberg SA, Schrump DS. Thoracic metastasectomy for adoptive immunotherapy of melanoma: A single-institution experience. J Thorac Cardiovasc Surg 140:1276-1282,2010 Read more »
Collaborating in the Multidisciplinary Research Program(s):