Originally from Malaysia, I graduated from the University of Arizona with my B.S. and M.S. in microbiology. I then worked in a private environmental lab for a few years before deciding to join graduate school. I joined the CMB Program in the fall of 2009 and work under Dr. Nicholas Heintz. Our lab studies the cell biology of mesothelioma, an aggressive cancer that presents itself on the mesothelium lining of the lungs. I hope to be able to discover novel therapy targets for the treatment of this disease.

Redox-dependent signaling by reactive oxygen species (ROS) plays an important role in cancer pathogenesis, and may represent a therapeutic target in malignant mesothelioma (MM). We have explored the role of FOXM1, a redox-responsive forkhead transcription factor that regulates cell cycle progression and resistance to oxidative stress, in MM cell proliferation and viability. Human MM tumors express more FOXM1 transcript than normal mesothelial tissue, and immunostaining of human MM tissue arrays confirms that FOXM1 is broadly expressed in all major subtypes of human MM. Studies show that MM cells in vitro constitutively generate approximately 2-fold more mitochondrial superoxide than control immortalized LP9 mesothelial cells. The triphenylmethane gentian violet (GV), the thiazole antibiotic thiostrepton (TS), and selected triphenylphosphonium (TPP) compounds inhibit FOXM1 expression and MM tumor cell viability in a dose–dependent manner. We have shown each of these agents targets different facets of the thioredoxin reductase 2 (TR2) – thioredoxin 2 (TRX2) – peroxiredoxin 3 (PRX3) antioxidant network, the predominate pathway for metabolizing hydrogen peroxide in mitochondria. GV targets expression of TRX2 protein, TS covalently adducts and inactivates PRX3, and TPP compounds inhibit expression of PRX3 and induce extensive mitochondrial fragmentation. In contrast, the general NADPH oxidase inhibitor DPI had no effect on FOXM1 expression. Studies in a xenoplant model of human MM in Fox Chase SCID mice show that TS and GV alone are marginally effective in inhibiting tumor growth, while a combination of the two compounds significantly impairs tumor progression without overt toxicity (p = 0.006). Our in vitro studies indicate that FOXM1 expression is tuned to an optimal flux of mitochondrial oxidant production, and agents that either markedly diminish or accentuate the production of mitochondrial oxidants inhibit FOXM1 expression. Since over-expression of the TR2-TRX2-PRX3 pathway is linked to resistance to apoptosis, and components of the pathways are known to be up-regulated in the majority of MMs, these studies offer a new therapeutic strategy for treating MM. Moreover, inhibition of PRX3 expression has been shown to sensitize cancer cells to common chemotherapeutic drugs, suggesting that alone or in selected combinations these agents may be useful in disabling a major adaptive response that contributes to MM drug resistance.