Traditional methods of targeting cancer by chemo- and radiotherapy have often been hampered by a difficulty in identifying appropriate drug or radiation targets and then a lack of selectivity and specificity in targeting them. A group of researchers led by Yicheng Ni from the University of Leuven, Leuven, Belgium has suggested an alternative approach: instead of targeting the cancer cells themselves ('seeds'), Ni and his co-workers propose attacking two targets within the stroma (the 'soil') that are closely associated with tumour cells and that tumour cells may depend on for their function. These are, first, the endothelium of the tumour vessels (which can be attacked successfully with antitubulin agents) and, secondly, areas of necrotic tumour tissue. This can be targeted using a newly-discovered range of 'necrosis-avid' compounds that can also be linked to therapeutic radio-nuclides such as Iodine-131 (131I). Any cancer cells left after treatment with a vascular-disrupting agent should be killed by beta-radiation from a radio-labelled necrosis-avid compound.

Ni and his co-workers have now tested their novel approach in a rat model of liver cancer. Twenty-four rats were implanted with rhabdomyosarcomas and randomised into four groups. One group, the dual-target group, received one injection of combretastatin A4 disodium phosphate (CA4P), a pro-drug of the vascular-disrupting agent combretastatin, and another of the necrosis-avid compound hypericin labelled with 131I. Two more groups received injections of one of these agents plus the solvent for the other, and the fourth, the dual control group, received only injections of the two solvents. Tumour growth was monitored in vivo using magnetic resonance and all rats were euthanised after one 131I half-life of eight days.

Comparison of tumour growth between the groups showed that, as expected, the tumours grew most rapidly in the rats in the dual control group. Rats injected only with CA4P showed early vascular shutdown and tumour necrosis followed by re-growth, and those injected with 131I- hypericin showed slow tumour growth. However, tumour growth in rats injected with both agents was inhibited effectively over the eight days. In the two groups of rats treated with the radionuclide, radioactive iodine accumulated mainly in necrotic liver tumour tissue. Some radioactivity was noted in non-necrotic tumour tissue, healthy liver, and other organs including the thyroid, and some was excreted in the faeces. However, uptake of 131I- hypericin was some 21 times higher in necrotic tumour than in healthy liver tissue.

In discussing their findings, Ni and his colleagues stress that tumour growth was inhibited after one dose of each of two agents and that the effect was much stronger than could be observed with either agent given independently. The strategy he adopted depends on firstly creating tumour necrosis by targeting the tumour vasculature and then delivering a second agent – the radio-therapeutic – to selectively target necrotic tissue. Vasculature and necrosis are features of the tumour micro-environment (here described as "soil" in comparison to the tumour "seeds") that are found in many tumour types, regardless of genetics or histology, so therapies that target them successfully may be applicable to a wide variety of cancers. Once fully validated and optimised, this strategy will be worth testing in clinical trials.

Reference

Li, J., Sun, Z., Zhang, J. and 21 others (2011). A Dual-targeting Anticancer Approach: Soil and Seed Principle. Radiology 260, 799-807. doi: 10.1148/radiol.11102120