School of Medical Sciences


Targeting the inflammatory cell infiltrate with IMiDs

IMiDs_70

The inflammatory cells in the tumour infiltrate release numerous growth and survival factors that are essential for tumour progression. A promising approach to cancer therapy targets the inflammatory cells to suppress their production of survival factors. The power of this approach is exemplified by the success of the IMiDs, thalidomide and its second generation analogue, lenalidomide, for treating multiple myeloma. Interactions between the myeloma cells and the bone marrow stromal cells, stimulate the release of factors that include IL-6, VEGF and TNF. The IMiDs disrupt the interactions between the myeloma cells and the bone marrow cells, and attenuate the production of the factors required for the myeloma cells to grow.                                                                                      

Previous work from our group investigated whether it was thalidomide or its metabolites that was the active agent. Of the three metabolites that could be detected in myeloma patients responding to thalidomide therapy (1,2), only one of the metabolites, known as CGI for short, showed an ability to modulate TNF and IL-6 production by cells in culture. Analogues of CGI have been synthesised at the ACSRC to develop compounds that are more active than thalidomide but with fewer side-effects. Promising new analogues will be evaluated in a transgenic murine model of myeloma.

Earlier work from our group demonstrated that thalidomide could potentiate the anti-tumour effects of DMXAA in a murine colon carcinoma model (3-5). Recent studies indicated that the second generation IMiDs also possess this activity. Since DMXAA and the IMiDs cross the blood brain barrier, we are currently investigating the activity of these drugs in combination for the treatment of brain cancers and brain metastases.

References


1. Chung, F., Lu, J., Palmer,B. D., Kestell, P., Browett, Baguley, B, C., Tingle, M., Ching, L-M. Thalidomide pharmacokinetics and metabolite formation in mice, rabbits and multiple myeloma patients. Clinical Cancer Res. 10, 5949-5956, 2004.

2. 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. 9, 1680-1688, 2003.

3. Cao, Z., Joseph, W.R., Browne, W.L., Mountjoy, K.G., Palmer, B.D., Baguley, B.C., Ching, L-M. Thalidomide increases both intra-tumoural tumour necrosis factor-alpha production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid. Br J Cancer 80, 716-723, 1999.

4. Ching, L-M., Browne, W.L., Tchernegovski, R., Gregory, T., Baguley, B.C., Palmer, B.D. Interaction of thalidomide, phthalimide analogues of thalidomide and pentoxifylline with the antitumour agent 5,6-dimethylxanthenone-4-acetic acid: concomitant reduction of serum tumour necrosis factor-alpha and enhancement of antitumour activity. Br J Cancer 78, 336-343, 1998.

5. Ching, L-M., Xu, Z.-F., Gummer, B.H., Palmer, B.D., Joseph, W.R., Baguley, B.C. 'Effect of thalidomide on tumour necrosis factor production and anti-tumour activity induced by 5,6-dimethylxanthenone-4-acetic acid.' Br J Cancer 72, 339-343, 1995.