Abstract
Dr Jean Plouët (Centre de Recherche Cardiovasculaire, INSERM U 689/Institut des Vaisseaux et du Sang) was interviewed by Emma Quigley (Commissioning Editor, Expert Opinion) on 20th June 2006. Born in Brittany, France, Dr Jean Plouët received his MD degree from Nantes University in 1977 and his PhD in Molecular Biology from Paris VII University in 1981. His first research topic, under the supervision of Dr Courtois and Dr Barritault was devoted to the purification and the description of the mechanisms of action of eye-derived growth factor, which turned out to be the retinal fibroblast growth factor (FGF)-2. He was appointed as Charge de Recherche by the Centre National de la Recherche Scientifique in 1981. He later conducted his research on the effect of FGF-2 on light transduction and demonstrated the role of opsin phosphorylation on FGF-2 release from retinal discs in Dr Pouliquen’s laboratory. From 1987 to 1989, Dr Plouët worked in the Cancer Research Institute at the University of California, San Francisco, in Dr Gospodarowicz’s laboratory where he co-discovered vascular endothelial growth factor (VEGF) with Dr Napoleone Ferrara. He established his own group in Toulouse where he worked on the mechanisms of action of VEGF and vascular targeting by anti-idiotypoc antibodies against VEGF and FGF. In 2005, Dr Plouët moved to Paris where he now works mainly on endogenous inhibitors of angiogenesis acting downstream of VEGF.
1. Why is angiogenesis such a popular area for cancer therapy research?
If we go back to the history of angiogenesis research, it was almost silent between the seventies and the early nineties. It was not until the discovery of VEGF in the nineties that there was a huge increase in the angiogenesis field. VEGF was claimed to be very specific for endothelial cells. One of the pivotal papers of the time showed that an antibody against VEGF alone was able to inhibit tumour growth in a mouse. At the time, it was not expected that inhibiting only one factor would actually inhibit tumour growth. This led to an increase in research in this area.
We are only at the beginning because we only have one class of compound, the anti-VEGF agents. We still don’t really know how this works and why a given patient would be more sensitive than another one. It is not like trastuzumab for instance, which is given only if a certain receptor is overexpressed. The main issue is for clinicians to be able to find a way to predict if a given patient will be sensitive or not, whether it is using pharmacogenomics or to find a circulating marker or circulating endothelial cells.
I would like to also raise the point that antiangiogenic therapy is not restricted to cancer. It has also been successful in age-related macular degeneration. There is already one anti-VEGF drug on the market for age-related macular degeneration, and another one, an antibody against VEGF by Genentech, which is currently awaiting FDA approval.
2. What are you currently working on?
Antiangiogenesis is such a popular area that there are at least 50 compounds in preclinical or clinical trials targeting the VEGF pathway; most of them are anti-VEGF. I do not work any longer on VEGF by itself, but I try to focus my research interest in two ways. One way is to discover the pathways downstream of VEGF. Another is look at other targets that are totally separate to VEGF. One target I work on is a protein call nephroblastoma overexpressed (NOV); the gene for this has no known function so far. We have found that it inhibits a pathway downstream of VEGF; the Notch pathway, which is responsible for the differentiation and migration activity of VEGF. We prepared this, made a fragment and showed that it is an antiangiogenic compound.
The second one is netrin 4, a molecule that is known to work in the nervous system to direct the position of axons. It is a guidance molecule. Netrin is Sanskrit for ‘the one who guides’. We found that netrin 4 is antiangiogenic.
3. Who are you working with?
The group of Anne Eichmann in the College de France in Paris is working on netrin 1 and angiogenesis and we are working together. We also have a strong collaboration with Dr Florian Sennlaub, from INSERM U 598, for the evaluation of NOV and netrin 4 in ophtalmological animal models. There is also some collaboration with the ophthalmologists, cardiovascular specialists and surgeons in our hospital Lariboisière.
4. How did you identify these targets?
Well, it is a different story for each of the molecules. For NOV, it was just by chance. I know Dr Maryvonne Laurent and Cecile Martinerie, researchers working on NOV, and it seemed there was a VEGF binding sequence. I looked at the antiangiogenic effect and determined that it is not by this sequence, but it is by disrupting the notch pathway downstream of VEGF.
For netrin 4, we made a search of genes which are upregulated in angiogenesis and we chose this one as it is very antiangiogenic. Many laboratories are using this type of experiment; the difficulty is to choose a good compound. Netrin 4 appears to still be active where bevacizumab fails.
5. What techniques are being used to research this?
We use conventional in vitro techniques. Our lab is mainly interested in the vascular remodelling, which occurs in the late stage of angiogenesis and we found that the best target cell is not capillary- or vein-derived endothelial cells; it is artery-derived endothelial cells. Netrin 4 has been shown to act only on arterial endothelial cells. We are also using conventional in vivo techniques.
6. Do you have a drug candidate based on either of these targets?
We have made two products. One works by shortening netrin 4. We also engineered a mutated netrin 4, which is 1000-times more potent that the wild-type netrin 4. We are working on developing these compounds.
7. What are the implications of this drug reaching the market?
There is a lot of room for other compounds that are not anti-VEGF compounds. If we look at clinical trials, ∼ 60% of patients do not respond to anti-VEGF drugs. The results for those patients who are sensitive to anti-VEGF drugs are very impressive but there are still those that are not, and we expect those people to be sensitive to the new drugs. There is a time when cancer will become resistant to the anti-VEGF drugs. It is the post-VEGF era we have to fear.
8. How will this compound compare with other therapies currently available?
We have found that netrin 4 has no effect on resting endothelial cells. We expect less toxicity in normal vessels. So far, we have seen no side effects but it is too early to predict anything as we are only working on mice.
9. How long have you been working on this?
We have been working on this for about two years now. I moved from Toulouse to Paris two years ago to establish a new laboratory. I am working in academia so this project needs to be developed by a company outside. This is in the process of being done. We would like to start clinical trials in the next two years. We are searching for collaboration with big pharma companies.
10. Who are your main competitors in this area, and how do their compounds compare with yours?
We can never know, but I suspect there is no competition for NOV. There are a few people working on netrin 4 but there are many other guidance molecules that have been discovered in the nervous system. Most of them have a role in angiogenesis.
11. What are the current hot topics in atherosclerosis research, and where do you see the field going in the coming years?
Although neovascularisation is critical for atherosclerotic plaque instability, it is ascertained that the stimulation of angiogenesis induces atherogenesis. Endothelial progenitor cells derived from bone marrow may actually prevent intimal thickening by repairing vascular injury. In the future, the importance of endothelial progenitor cell therapy will have to be evaluated carefully.
12. Please provide your Expert Opinion on inhibiting angiogenesis
I am very happy to have seen the discovery of VEGF. I am a co-discoverer of VEGF with my co-worker Napoleone Ferrara when we were at UCSF. We were lucky to have the opportunity to see the fundamental research of a compound at the beginning which is now a success in the clinic. Within the next decade there will be a lot of different antiangiogenic compounds targeting other pathways. That is why it is so important to find new targets, not only downstream of VEGF, but of undiscovered genes of importance.
Contact details
Jean Plouët is team leader ‘angiogenesis and therapeutic targeting’, and can be contacted at Centre de Recherche Cardiovasculaire, INSERM U 689/Institut des Vaisseaux et du Sang, Hôpital Lariboisière, 8 rue Guy Patin, 75010, Paris, France, by telephone (+33 01 53 21 67 41) or email ([email protected]).