Our lab is currently focused on two different areas of cancer biology research. The first is to study the potential application of molecular therapy in the management of patients with nasopharyngeal carcinoma (NPC). Over the years, we have evaluated the role of wild-type p53 gene therapy in NPC, using an adenoviral vector (1-3). It is clear that this strategy is effective in vitro, particularly when combined with other cytotoxic modalities, such as ionizing radiation (1, 2), chemotherapy (4), or hyperthermia (5). We have also evaluated the p16 cell cycle gene, and observed that it is highly efficacious in NPC whereby p16 expression is absent in both EBV-negative (6), and EBV positive models (7). However, these approaches are more limited when evaluated in 3-dimensional tumour models (8).

To address this challenge, we have developed a novel construct, modifying the promoter so that we can exploit the presence of the Epstein Barr virus (EBV) in NPC cells, to achieve tumour-specific expression (9). We are the first group to have successfully generated this construct, and demonstrated its specificity both in vitro and in vivo.

Building upon this platform, we have just successfully generated and evaluated a conditionally replicative adenoviruses (CRA), specifically under the control of the EBV-responsive promoter. This indeed achieved viral oncolysis specifically in EBV-positive cancer cells, and in combination with local tumour radiation, we observed tumour regression for several weeks' duration (Chia et al, submitted).

Using this same tumour-targeting strategy, we have also evaluated the potential role of novel apoptotic genes. The utilization of FasL, achieved temporary disappearance of NPC xenografts, when treated in combination with radiation (10). We have just completed the assessment of Bims, a novel mitochondrial apoptotic gene (Yip et al, submitted), and Pidd, a p53-inducible death gene (Li et al, in preparation).

During this time, we have also evaluated BLI (bioluminescence imaging) as a tool to expeditiously track the kinetics and biodistribution of our novel vectors longitudinally, in real-time. This technology is based on the firefly luciferase reporter gene, and the signals are captured on a CCCD (cooled charged coupled device) camera. Future efforts will focus on a combinatorial strategy of CRA with novel therapeutic genes, and determining the efficacy and toxicity profiles of these innovative approaches.

Additional projects currently involve the generation of different types of CRAs, and chimeric adenoviruses. We are also embarking on examining the potential of siRNA technology against EBV-specific targets, in addition to an anti-sense oligonucleotide approach. The ultimate objective is to translate our 'best laboratory invention' into Phase I & II clinical testing for NPC patients within the coming years.

Our second area of research activity is focused on translational studies in NPC. Using primary human samples of NPC, we are one of the first groups to document the strong association between p53 over-expression and EBV in NPC cells, which in turn, correlated with a more favourable response to radiation therapy (11). We have also demonstrated that absent p16 expression was also associated with reduced survival (12). We have just embarked on utilizing the cDNA micro-array technology, to attain some understanding on the pathogenesis of NPC, with the anticipation of identifying novel molecular targets, which could offer therapeutic opportunities.

Additional areas we have been investigating include using heat as a targeting strategy, in the treatment of human breast cancer models (13, 14), with the use of suicide or fusogenic genes as therapeutic targets (15). We have also evaluated prognostic markers in breast cancer, and identified that the PTEN-PKB pathway is dysregulated in approximately 1/3 of patients with lymph node negative breast cancer, which in turn, is associated with negative ER/PR status (16).

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