Cut the lifeblood

Having dedicated decades to developing chemotherapies that target a wide range of cancers - one of the 10 leading causes of death globally - researchers are now focusing their efforts on developing more targeted therapies, including a new class of medicines referred to as 'vascular disrupting agents' (VDAs), also known as 'vascular targeting agents'. 

It is well established that a functioning vascular supply is essential for solid tumour growth and metastasis, and that in the absence of a viable vascular network tumours are unable to grow beyond a few millimetres, therefore remaining dormant.VDAs have significant potential to restrict the blood flow to a tumour selectively, which would otherwise feed its growth.

Development of agents that target and destroy existing tumour vasculature is gaining momentum, as research strives to improve upon, and add to, the existing therapeutic arsenal. One such agent is DMXAA (5,6-dimethylxanthenone-4-acetic acid), a small-molecule analogue of mitoflaxone (flavone acetic acid).

DMXAA was discovered by Professors Bruce Baguley and William Denny, plus other researchers from the Auckland Cancer Society Research Centre at the University of Auckland in New Zealand. The UK-based biopharma company, Antisoma, currently holds the worldwide rights to the product.

The first clinical trial of DMXAA was conducted in 1996 in New Zealand and the UK. Phase II trials of DMXAA in combination with standard chemotherapy have been conducted in patients with non-small cell lung, prostate and ovarian cancers in New Zealand, Australia, Europe and the US.

Endothelial damage
Although the exact mechanism of action of DMXAA has yet to be fully elucidated, it appears that it acts directly on endothelial cells that line tumour capillaries, causing damage that, in turn, leads the capillaries to leak. The blood supply to the tumour slows and then stops altogether, depriving the cells of oxygen and resulting in cell death (apoptosis).

The indirect actions of DMXAA appear to include the release of von Willebrand factor (leading to the clotting of blood and the occlusion of blood vessels) and additionally to the activation of tumour-associated macrophages to release various immunostimulatory cytokines and
chemokines (eg, tumour necrosis factor and serotonin).

Both the direct and indirect effects of DMXAA culminate in the breakdown of the vasculature and the death of tumour cells by haemorrhagic necrosis.

Results to date
Data from three, randomised, open-label phase II trials of DMXAA in patients with non-small cell lung cancer (NSCLC), ovarian and prostate cancers were reported during September and October last year. In each of the clinical trials, administration of DMXAA in combination with standard chemotherapy resulted in more favourable treatment responses than those following administration of standard chemotherapy alone.

In the NSCLC trial, 37 patients with stage IIIb/IV disease treated with DMXAA in combination with carboplatin and paclitaxel achieved a median survival time of 14.0 months, compared with 8.8 months among the 36 patients treated with carboplatin and paclitaxel alone. Patients who received the DMXAA combination also experienced increased tumour response rates and a longer time to disease progression.

In the ovarian cancer trial, a tumour response rate of 75 per cent was achieved by 39 patients treated with DMXAA combined with carboplatin and paclitaxel, compared with only 63.2 per cent of the 38 patients treated with carboplatin and paclitaxel alone.

Finally, in the prostate cancer trial, data from the first 64 of the expected 74 patients with hormone-refractory, metastatic cancer showed a prostate-specific antigen response rate of 57 per cent among those treated with DMXAA combined with docetaxel, compared with only 35 per cent in those on docetaxel alone.

Safety data from all three trials have shown that DMXAA in combination with standard chemotherapy was well tolerated. While the trials in patients with ovarian and prostate cancers are ongoing, the phase II NSCLC trial has now been completed and Antisoma is preparing for phase III trials for lung cancer.

Other VDA candidates
There are two types of vascular disrupting agents: small-molecule agents (eg, DMXAA); and biological or ligand-directed agents (eg, antibodies, peptides, growth factors). While there are only a limited number of vascular disrupting agents in clinical development, DMXAA is the most clinically advanced compound of this class of anti-cancer agents.

To date, development of small-molecule, vascular disrupting agents has been focused primarily on flavonoids and tubulin-binding agents. Key small-molecule agents currently in clinical trials include: combretastatin A4 (OXiGENE: phase II for breast, ovarian and lung cancers); OXi 4503 (OXiGENE: phase I for solid tumours); MN-029 (MediciNova: phase I); and AVE-8062 (sanofi-aventis: phase I for solid tumours).

There is considerable work to be done before DMXAA can reach the marketplace. While vascular disrupting agents have demonstrated antitumour effects and tumour core necrosis, they consistently leave a thin rim of viable tumour cells at the periphery of the tumour.

Evidence suggests it is likely that DMXAA will achieve its greatest effects when co-administered with standard chemotherapy regimens or other modes of treatment in order to attack this outer rim of tumour cells.

The author
Pipeline was written by Asha Vaidya of Adis International, using data derived from Adis Clinical Trials Insight and R&D Insight.