PROGRESS IN DEVELOPING DRUGS THAT TARGET TUMOUR BLOOD VESSELS
For tumours to grow larger than a few millimetres in size, it is necessary for them to develop their own blood supply. There are two fundamentally different approaches to targeting blood vessels that supply tumours. The approach that is most developed is aimed at preventing new tumour blood vessels from growing and is called anti-angiogenesis. Several drugs such as bevacizumab and sunitanib and pazopanib are already licensed for use in different tumours. The other approach uses drugs, called vascular disruptive agents, to selectively damage the blood vessels already supplying cancers so that the blood flow to the cancer can be stopped and the cancers rapidly die.
The CTRT has made a major contribution into funding trials of vascular disruptive agents, commonly known as VDA’s. In the 1990’s it supported trials of vadimezan (also known as DMXAA and AS1404) which was developed in New Zealand. The original first in man phase I trials were carried out at Mount Vernon Hospital, Bradford Royal Infirmary and in Auckland, New Zealand organised by Cancer Research UK. Early results suggest that it could reduce blood supply to tumours in some patients. This drug was licensed to Antisoma and then Novartis organised world-wide clinical trials. Unfortunately these trials did not show that this drug was as effective as was initially expected.
The CTRT in collaboration with CRUK then ran clinical trials of fosbretabulin (also known as combretastatin A4 phosphate -CA4P) and then trials of OXI4503. These trials used special MRI scans to show that these drugs could shut down the blood supply to human cancers within a few hours. The initial trials showed that these drugs had unusual side effects, such as raising blood pressure and causing acute pain in cancers, presumably due to the lack of oxygen. Although OXI4503 appeared the most powerful it was considered rather toxic, so we are continuing development with fosbretabulin.
Laboratory studies showed that these drugs work best when given in combination with cytotoxic drugs or radiotherapy. This led to combination trials being run at Mount Vernon Hospital and supported by CTRT. More recently it has been shown that certain drugs that target VEGF can prevent the re-growth of viable cells that survive the initial VDA therapy. This has led Professor Rustin to propose trials that combine VDA therapy with anti-angiogenic agents. A trial of fosbretabulin combined with pazopanib started in October 2014 for patients with relapsed ovarian cancer at Mount Vernon, Royal Marsden and Christie Hospitals. After treating the first 12 patients it was clear that the combination of drugs is active and it was possible to select the correct dose for a randomised trial. This started in 10 UK centres in 2016, but was stopped after recruiting 21 patients. Although there was obvious anti-tumour effect with the combination there were three reversible cardiac events. This unfortunately led to Novartis who supplied the pazopanib to close the trial. The CTRT remains committed to fund the translational research associated with this trial as well as the research staff working on this trial at Mount Vernon.