New Drugs

There are new drugs on the market today and in clinical trials that I believe will present some dynamic new treatment options for people with VHL. To get from here to there will take a great deal of patience, research, and clinical trials, but the next three to five years will be an exciting time. The study of angiogenesis, the way the body creates new blood vessels, is a key focus for VHL research and for cancer research in general.

Without a new blood supply, tumors can’t grow beyond one millimeter in diameter, they can’t spread to the rest of the body, and they can’t grow at other sites in the body. The study of angiogenesis is a really hot area for developing anti-cancer drugs.

My main interest is in dealing with solid cancer tumors. But I recently joined the VHL team in Oxford, and have started to develop new studies to try and help patients with VHL, as part of an international collaborative effort.

We have heard a lot about the protein Vascular Endothelial Growth Factor, or VEGF, which the body normally generates when tissues need more oxygen. If you have a stroke, heart attack, or other injury, your body switches on VEGF to help repair the blood supply.

Angiogenesis is regulated in other ways as well -- so far at least seven different pathways have been identified, of which VEGF is probably the most important, as it makes the others work better. Blocking one of these pathways can help reduce the effectiveness of the others.

The amount of VEGF is much higher in most cancers than in normal tissues, and it predicts outcomes. If a cancer tumor has a lot of VEGF associated with it, it will grow more rapidly and there are more blood vessels. All of this has been good evidence that VEGF is a good target for treating cancer, and there should be some spinoff benefit for treating VHL.

VEGF comes out of the cancer cells and binds to receptors on the surface of the blood vessels to get them to grow. We can block the receptor signaling with a drug that’s called a receptor kinase inhibitor. Sugen’s drug SU5416 is one of these receptor kinase inhibitors. But there are also other approaches we could take that might have the same effect. We could block the receptor, destroy the VEGF, or destroy the blood vessels themselves.

All these approaches are now in early, or "Phase 1", clinical trials. But we don’t actually know the safe dosage levels of the drugs involved. We begin with a very low dose and gradually build the dose up in successive groups of patients. If you have VHL, you don’t want to be in Phase 1 because you’re likely to need long-term treatment. You want to know the right dose, and the safe dosage level. So we need to take the lead from the cancer trials and apply those results across to VHL. In our early studies with SU5416 we have accepted only very severe cases of VHL, where there is no standard treatment that will make things better.

What are the drugs available? We do not yet have any drugs directly helpful for VHL. There are some drugs on the market today for other things that also have anti-angiogenic properties. Interferon, which is a standard treatment for kidney cancer, is used to treat rare blood vessel syndromes in childhood. Thalidomide, which is becoming more widely used in cancer, seems to be able to block the blood supply to tumors, but is toxic to nerve tissue in long-term use. It can cause fetal malformation, so if you use it you have to use two forms of contraception. Captopril is used to treat hypertension. And there’s a new sort of anti-inflammatory drug known as a Cox-2 (cyclooxygenase) inhibitor which has recently been shown to prevent development of colon cancer from colon polyps.

These drugs are not very potent, but they do have some anti-angiogenic activity. Of those thalidomide is the most potent, but is difficult to use in the long term. Interestingly, these drugs that block blood vessel formation do not block wound healing. It may be that wound healing uses multiple pathways and blocking one is not enough. In other words, the drugs currently on the market are certainly not optimal for VHL. They were not designed to block angiogenesis, they are not specific to VHL, they are toxic, and there is little data to support them apart from thalidomide.

In our current study, we wanted to get the latest VEGF kinase, to block the receptor for VEGF. It is not easy to get access to these drugs for rare diseases. Most drug companies are concentrating first on cancer, because cancer is big business. It takes a lot of persuasion to test the drugs for rarer diseases. Because our team is very actively involved in drug trials for cancer patients with VEGF inhibitors, we have been able to persuade companies to link up with us to do this kind of specialized test. Sugen is also linked up with Dr. William Kaelin in Boston, and with trials in Poland and France. This is what we call a pilot study. We did it to get experience on safety and toxicity at the top dose used to treat cancer patients, to make sure that VHL patients tolerated it well, and that it was compatible with their lifestyle, before beginning a proper Phase 2 trial.

The Sugen drug is a small molecule. It has to be given intravenously. There will be a version of this in 2001 that is oral, and there are at least two other companies with oral versions coming through, and within 2-3 years there will be much better ones. It is a rapidly changing field, and we need to convince companies to support us with the latest drugs once they have the Phase 2 levels available.

We have tried SU5416 with three patients in very grave condition, and one patient with a serious eye tumor but otherwise in relatively good health. Two stabilized but did not improve, and in two patients the lesions stayed the same but the symptoms got worse. So it’s very early days. We need to recruit a larger number of patients in multiple centers. We also think that when we begin to treat patients earlier in the disease process, we should have more success.

Level of activity. One of the challenges is to detect the level of activity biochemically in the lesion. Can we tell if it has stopped growing, or become less active? We are trying various techniques that have been developed for treating common cancers to see if we can apply them to the VHL lesions to get an indication of activity. One is to use special techniques of MRI to measure uptake and diffusion of the contrast agent, which tells us about the blood flow and the vascular permeability. Cancer tumors with a very high uptake rate may respond to SU5416. It may be that after VHL tumors have been there for many years and the blood vessels are very well organized, it may be much harder to get them to shrink away. In people with VHL you have a mixture of leaky vessels which you might be able to modify, and old vessels that are well differentiated and that will be hard to shrink.

Tissue Bank donations are very important, because we really need to know more about what’s going on in these different tissues. Various tumors have different rates of growth -- some speed up, some stay stable -- and thre is great heterogeneity here. We would like to analyze many tumors to see if we can predict which ones will grow and which ones will remain stable.

Positron emission tomography (PET) scanning, is offering some very interesting possibilities. We are using an antibody to VEGF and labelling it so that it shows on PET scans. We inject the tracer into patients with cancer, and on the scan we can see the individual lesions which are making VEGF, and the levels of VEGF in each, without having to biopsy or stick a needle in the lesions. All the lesions light up with varying intensity indicating the relative levels of VEGF. This antibody is now in clinical trials for cancer treatment. As we get more experience with it we will want to move on to VHL patients to see if the lesions differ in the amount of VEGF they make. Our thought is that this might determine why they are behaving in different ways.

There is a long list of other proteins known to be regulated by VHL, all of which are known to be important in tumor angiogenesis and might be important in VHL angiogenesis. We just don’t know yet. We’d like to analyze a wide variety of lesions to see if any of these factors are actually switched on or not. There are drugs that will block most of these, either on the market or now in cancer therapy trials. It will be important to understand which of these pathways are the most important, and to understand the heterogeneity.

We have all seen the heterogeneity in VHL – different kinds of tumors, different growth rates, variations between families, between patients within families, and between lesions in the same patient. Obviously there are multiple things going on. Similarly in cancer understanding heterogeneity is important. Our team did a study correlating the number of blood vessels around a cancer tumor with the long-term outcome of the patient. We just counted the number of blood vessels, and the higher the number of blood vessels in a cancer the worse they did. We also found that there was an even higher correlation between high concentrations of VEGF and more aggressive cancers. Similarly in VHL, if there is a variability in the amount of VEGF made or bound by lesions, this might explain some of the variability we see, and might help us understand which drugs we might need to use.

In conclusion, anti-angiogenesis therapy is a rational approach to VHL. Long-term use may be necessary. Drugs blocking VEGF are the highest priority, but we should not ignore other pathways. And we may not be able to regress established vessels, which would be an argument for treating early. A broad spectrum or combination of drugs may be the most useful, to block multiple pathways. But we do need more investigation into the pathways involved in blood vessel formation. If VEGF turns out to be a key driver, as we think, in the formation of renal cysts as well, then the controls we use for hemangioblastomas might prevent the loss of kidneys as well.

There is a lot happening out there, and there is much to learn about the applicability of these new cancer drugs to the treatment of VHL. As soon as we know the right doses of a drug, and something about its safety, we will initiate trials. The next three to five years will tell us a lot about long-term safety in cancer, with direct application to VHL and the prevention of cancer.

Dr. Harris is Professor of Clinical Oncologist, Churchill Hospital, associated with Oxford University in England.His work is supported by the Imperial Cancer Research Fund in the U.K. This article is based on his talk at the VHL Symposium, July 2000.

As printed in the VHL Family Forum Research Report 8:5, December 2000.  For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.