VASCULAR DISRUPTING AGENTS

 

Over 90% of all cancers present as a solid tumour mass that is dependent on a functioning blood vessel network to supply oxygen and nutrients and to remove waste products. Cancer cells stimulate blood vessels to grow into the developing tumour by a process called angiogenesis. Factors released by the tumour cells stimulate the endothelial cells in surrounding normal tissue to divide and migrate, creating new blood vessels that supply the growing tumour with its essential nutrient requirements. It is well established that in the absence of angiogenesis, the size of a tumour cannot exceed 1 mm3. If angiogenesis is successfully initiated, the tumour continues to grow but such growth and survival is totally dependent on the continued functional integrity of the new blood vessel network. This dependence can be demonstrated by the fact that if the blood supply to a tumour is mechanically shut off, massive cell death occurs and the cancer dies away.

 

Angiogene's vascular disrupting agents cause rapid and irreversible shutdown of bloodflow in solid tumours by destruction of established tumour vasculature. Normal tissue blood vessels are largely unaffected, as, unlike tumour blood vessels, they are mechanically stable and the endothelial cells that line them are resistant to disuption of the tubulin cytoskeleton. The consequence of bloodflow shutdown is massive tumour cell death that, importantly, obliterates the centre of the tumour. It is this central region that contains the hypoxic cells and thus vascular disrupting agents address a major source of resistance to conventional therapy. The remaining outer cells are well oxygenated and sensitive to conventional treatment and it is expected that vascular disrupting agents will be particularly useful in combination with chemotherapy and radiotherapy.

 

Since vascular dirupting agents act directly on the endothelial cells in contact with the bloodstream there is no need for them to penetrate the tumour tissue itself; difficulties in penetration are another barrier to efficacy of some chemotherapy drugs. The target endothelial cells, unlike the tumour cells themselves, are normal host cells and therefore far less liable to the genetic plasticity that can give rise to mutation and resistance to conventional chemotherapy. Also, whereas a cytotoxic agent needs to kill the vast majority of tumour cells to be effective, the disruption of only a few endothelial cells in a vessel can completely compromise its function. There are thus many advantages to this new and exciting technology.

 

Angiogene currently has two vascular disrupting agents in clinical studies for the treatment of solid tumours : ZD6126 (licenced to AstraZeneca) and MN029 (licenced to MediciNova). Another series of compounds, the ANG500 series, is being developed for ocular neovascularisation disorders.

 

NOS INHIBITION

 

A few tumour models have been found to be insensitive to tubulin binding vascular disrupting agents. Angiogene's research has demonstrated that suppression of nitric oxide formation, by inhibiting the enzymes that form it (nitric oxide synthases, NOS), can restore sensitivity in these tumour models. Nitric oxide is thought to be protective against the damage caused by vascular disrupting by a number of mechanisms:

 

  • NO acts as a vasorelaxing factor, helping to keep the vessels open
  • NO downregulates the adhesion and activation of inflammatory leucocytes, thus preventing fixation of the initial damage
  • NO suppresses cell respiration to a level at which the cell can survive under conditions of limited oxygen supply

 

Nitric oxide also promotes both retinal and choroidal neovascularisation. Thus the combination of NOS inhibitors with vascular disrupting agents may lead to enhanced efficacy in both the solid tumour and ocular indications. Angiogene has patented the use of this combination as well as a number of proprietary compounds that combine both activities.

 

Licensees to this technology currently include AstraZeneca and MediciNova.

 

HYPOXIA-ACTIVATED PRODRUGS

 

Failings of conventional chemotherapy include inability to selectively target the cancerous cells, inability to penetrate tumour tissue and inability to overcome the resistance of hypoxic cell populations. Angiogene's Hypoxia Acxtivated Prodrug technology seeks to address these failings by generating cytotoxic drugs that are released by fragmentation from inactive prodrugs, selectively in the hypoxic regions of solid tumours. Since we target levels of hypoxia that are common in tumours but very rare in normal tissues we achieve selective targeting of the tumour. The more resistant, hypoxic, cells are exposed to the higher concentrations of released cytotoxic agent, which can also diffuse into the more oxygenated regions. As a major barrier to tumour penetration is binding to target proteins and DNA, the inactive nature of the prodrugs may also enhance penetration.

 

Angiogene is applying this technology to cytotoxic drugs from a wide variety of classes including nucleoside analogues, tubulin binding compounds and topoisomerase inhibitors. This research is conducted in collaboration with a group of scientists at the Gray Cancer Institute under the direction of Professor Peter Wardman. Professor Wardman has many years' experience in the chemistry of bioreductive drugs and radiosensitisers.

All images and text © Angiogene Pharmaceuticals Ltd. Last updated July 15th., 2007