Primary Appointment

Research Interests

We currently have two major research programs in our laboratory:

(A)  Improving the Therapeutic Efficacy of Platinum-Based Antitumor Agents

Platinum (Pt)-based antitumor agents have significant antitumor activity in the treatments of many human malignancies.  Especially in ovarian cancers and in testicular germ cell tumors, cisplatin (Cp)-based combination chemotherapy has been a pillar of drug therapy of these diseases.  However, resistance to these agents is the major cause of treatment failure. While it has been recognized that multiple mechanisms are involved in Cp resistance, one important mechanism of resistance is defective in drug transport.  Recent studies have indicated that the human high-affinity copper (Cu) transporter 1 (hCtr1) is a functional transporter of cisplatin and its analogues, carboplatin, and oxaliplatin.  Results from our laboratory have demonstrated that many established cisplatin (Cp)-resistant (Cp^R) cell lines exhibit reduced expression levels of hCtr1 compared with their matched parental cell lines.  These Cp^R cell lines can be re-sensitized to Cp treatment by overexpressing hCtr1 in these cells.  Our research interest has been the molecular mechanisms of hCtr1 regulation in mammalian system.  Copper is an essential micronutrient that is required for cell survival; yet Cu overload is toxic.  To meet their need for copper while avoiding copper toxicity, all living organisms from yeast to humans have developed an evolutionarily conserved system to regulate copper homeostasis.  We have been investigating mechanisms of hCtr1 regulation by copper homeostasis and how copper homeostatic regulation affects cancer cells to response to platinum-based antitumor drugs.

(B)       Improving the Chemotherapeutic Efficacy of Melanoma by Antitumor Agent Arginine Deiminase

Malignant melanoma of the skin can be highly lethal when the disease is detected in the advanced stages. Currently, overall cure rate for advanced melanoma is <10%.   It has been demonstrated that a great majority of malignant melanoma is autotrophic for arginine, due to the fact that these melanoma cells do not express argininosuccinate synthetase (AS), the rate-limiting enzyme for the biosynthesis of arginine from citrulline.  These AS-negative melanoma cells require arginine from extracellular sources for survival.  When these melanoma cells are exposed to arginine deiminase (ADI) which degrades arginine to citrulline and ammonia, they become arginine starvation, leading to cell death; while normal cells which express AS are able to survive.   ADI is a bacterial enzyme and a pegylated enzyme (ADI-PEG20) has been developed.  Favorable results from Phase I and Phase II clinical trials using ADI-PEG20 for advanced melanoma have been obtained.  It has been learned from clinical studies that not all the patients who are negative for AS expression responded to the ADI-PEG20 treatment.  Re-expressed AS has been observed in the ADI-insensitive patients.   Our research interest is the molecular mechanisms involved in the induced AS expression in melanoma cells exposed to ADI-PEG20 and to develop strategies to overcome drug resistance associated with AS induction thereby improving the efficacy of in melanoma cancer chemotherapy using ADI-PEG20.

Academic Appointments

Last updated: 9/2/2010