Stromal Targeting Agents website

Background

Associate Professor Lai-Ming Ching obtained her BSc, MSc (Hons), and PhD in Cell Biology all from The University of Auckland. Following a period after graduation at the Ontario Cancer Institute in Toronto, and The University of Washington in Seattle, she returned to New Zealand to a position at the Centre in the Biology Section to investigate the mode of action of novel drugs developed at the Centre.

Research Interests

With her background in immunology, A/Prof Ching specialises in the study of drugs that act through the body's own defence systems, and has had a long-standing involvement in elucidating the mode of action of one such drug developed at the Centre, DMXAA which is currently in phase III clinical trials. Her work showed that DMXAA stimulated host cells and tumour cells to release a number of different cytokines within the tumour site. Different cytokines produced within the tumour led to the promotion of tumour vascular damage, increase in cytotoxic immune cell activity, and the inhibition of endothelial cell neo-vascularisation. Current work is focussed on identifying the signalling pathways and biochemical target(s) activated by DMXAA.

Another drug that is being investigated by A/Prof Ching's group is thalidomide, an anti-angiogenic/anti-inflammatory agent remarkable activity in the treatment of multiple myeloma. Recent work from her group identified a metabolite of thalidomide in myeloma patients that shows anti-angiogenic and anti-inflammatory properties but lacks some of the undesirable side-effects of thalidomide. Her group is currently evaluatiing the activity of novel analogues of the metabolite synthesised at the ACSRC, for the treatment of multiple myeloma. This work is being carried out in collaboration with investigators at the Mayo Clinic, Scottsdale, AZ, USA.

Overcoming tumour-induced immune suppression with inhibitors of the enzyme indoleamine 2,3-dioxygenase (IDO) is a third area of research interest, and her group is currently establishing the in vitro and in vivo assays to support the evaluation of novel IDO inhibitors for use in combination with cancer vaccines.

Selected Publications

• Wallace, A., LaRosa, D.F., Kapoor et  al. The vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA), directly activates dendritic cells through a MyD88-independent mechanism and generates anti-tumor cytotoxic T-lymphocytes. Cancer Res. 2007, 67, 7011-7019.
• Palmer, B.D., Henare K., Woon, S-T. et al. Synthesis and biological activity of azido analogues of 5,6-dimethylxanthenone-4-acetic acid for use in photoaffinity labeling. J Med. Chem. 2007, 50, 3757-3764.
• Roberts, Z.J., Goutagny, N., perera, P-Y. et al. The chemotherapeutic agent 5,6-dimethylxanthenone-4-acetic acid, potently and specifically activates the TBK1-IRF-3 signalling axis. J Exp. Med. 2007, 204, 1559-1569.
• Wang, L-C.S., Woon S-T., Baguley, B.C., Ching, L-M. Inhibition of DMXAA-induced tumor necrosis factor production in murine splenocyte cultures by NF-kB inhibitors. Oncology Research, 2006, 16, 1-14.
• Jassar, A.S., Suzuki, E., Kapoor, V. et al. Activation of tumor-associated macrophages by the vascular disrupting agent 5,6 dimethylxanthenone-4-acetic acid (DMXAA) induces an effective CD8+ T-cell-mediated anti-tumor immune response in immunogenic and non-immunogenic murine models of lung cancer and mesothelioma. Cancer Res. 2005, 65, 11752-11761.
• Chung, F., Lu, J., Palmer,B.D., Kestell, P., Browett,P., Baguley, B,C., Tingle, M., Ching, L-M. Thalidomide pharmacokinetics and metabolite formation in mice, rabbits and multiple myeloma patients. Clinical Cancer Res. 2004 10, 5949-5956.
• Lu, J., Helsby, N., Palmer, B.D., Tingle, M., Baguley, B.C., Kestell, P., Ching, L-M. Metabolism of thalidomide in liver microsomes of mice, rabbits and humans. J Pharmacol Exp Tox. 2004, 310, 571-577.
• Ching, L-M., Zwain, S., Baguley, B.C. Relationship between tumour endothelial cell apoptosis and tumour blood flow shutdown following treatment with the antivascular agent DMXAA in mice. Br J Cancer. 2004, 90, 906-910.
• Lu, J., Palmer B.D., Kestell, P., Browett, P., Baguley, B.C., Muller, G., Ching, L-M. Thalidomide metabolites in mice and patients with multiple myeloma. Clinical Cancer Res. 2003, 9, 1680-1688.
• Ching, L-M., Cao Z., Kieda, C., Zwain, S., Jameson, M.B. and Baguley, B.C. Induction of endothelial cell apoptosis by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid. Br J Cancer. 2002, 86, 1937-1942.