Dominique Lallemand, scientist working on NF2 (Institut Curie, Paris)
We met Dominique Lallemand through Twitter. In our search of agents from the NF2 community, we find this french scientist who agreed to be written interviewed. He clarifies and develops the processes of persistent concern among the affected: how the research is carried out to get treatment.
How long are you dedicated to study the NF2? Was there progress at this time?
I started working on NF2 in 1999, in Boston (US), I was a student (post doc) in Andrea McClatchey lab. At that time, the NF2 gene had been identified five years earlier and almost nothing was known about the function of merlin. The mouse models had just been generated and we had the confirmation that the loss of NF2 in the mouse was leading to the development of tumors. That was an important step because it showed that we could use these mice to study NF2.
We didn't know at the time what was the function of merlin in the cells in general and in the Schwann cells in particular. Merlin was a very unconventional tumor suppressor because it was not an enzyme It was closer to structural proteins. Progressively, using celular models we started to understand what was the role of merlin in the cells. Important advances came from laboratories working on NF2 gene in drosopila (flies) that we could confirm and expand in our mammalian models, cells and mice.
Then, what is your opinion about the mice models to study human schwannomas?
The mouse models of schwannomas are a fantastic tool to study the disease. They are very essential to understand how de tumor develops and why. They are the source of crucial tools (such as Schwann cells we use in culture) for the research. However, I think that these models are not ideal to test drugs and this raise some problems in my opinion. These mouse models do no reflect the diversity of the patients population. All the mice used are genetically identical (whereas patients are extremely diverse), they have the same NF2 mutation (patients have very different mutations that lead to different severity of the illness), they always develop the same tumors and disease. In a sense, they represent only one patient. They cannot be used to evaluate if a treatment is good or bad for a patient. They are very unlikely to be predictive models. A treatment that is efficient on a mouse model could be inefficient on the majority of the patients. Worse, what if a drug candidate doesn't work with mice? Should it be abandoned? Are we sure it wouldn't be efficient on a population of patients that are not represented properly by our mouse models? It is extremely difficult to generate enough mouse models to reflect the heterogeneity of the patients. It would take a lot of time and resources, probably too much. We should develop other types of models for drug testing such as xenografts models which consist of implanting pieces of human tumors in mice. This approach is the leading one for research on breast cancer, colon cancer and many others and reflects the diversity of the patient much more efficiently although it has some drawbacks. I think we should be extremely careful on the use of mouse models to test drugs. In addition, this activity is very expensive and drains money that sometimes could be better used in other area of NF2 research.
How is the job of your lab?
In our lab, we do essentially basic science. Our job is to understand what are merlin functions in a cell and why a tumor forms when merlin is absent. To do so, we use cellular models and mouse models. The general idea is that if we better understand the mechanisms of the formation of the tumors, we should be able to identify therapeutic targets. This is a relatively long term approach. It takes time to do these studies and there is not always a drug against the target that we identify. We also have a second approach which is a more direct one. We collect tumors from patients, in collaboration with clinicians (especially my colleagues Michel Kalamarides who is neurosurgeon and Anne Couvelard who is anatomopathologist, both in Paris). We essentially collect schwannomas but also meningiomas. We compare them to normal tissues to identify molecular dysfunction in the tumors. This is a more direct way to identify therapeutic targets. It is also a more short term approach because we try to focus on targets for which drugs already exist and could be use in the near future. But these studies also provide important informations that can lead to the development of basic science projects. So, basic science and applied science really enrich each other. Our last publication in the journal Neuro oncology is an example of that approach. Some of the results and a link to the publication are given on my Twitter account. Finally, we also try to identify compounds that could be active against some of the therapeutic targets that we have identified. This work can lead to the development of new drugs for patients although this is a long process. In the more short term, the compounds can also be used to do basic research on NF2.
Can you tell us about your exhibition in the 16.º European NF Meeting in Barcelona?
The NF Barcelona meeting was a very interesting and pleasant experience. The quality of the talks was very good. Of course, I would have hoped that there are more NF2 presentations. The meeting was good and I hope it will be advertized broadly so that our colleagues from the other continent would join. We need to have a strong NF meeting in Europe, as strong as the US one, because the research being done in Europe is as good and we need to develop the interactions and collaborations. Personally, I think that the interaction with the patients is essential for a scientist working on a disease. The interaction between scientists and clinician is also essential. I hope that future NF meetings will include sessions were scientist and patients groups can meet and also session between scientist and clinicians. It is important that patients understand what we do, and as important that we meet the persons we are working for (the patients). Using social networks, such as Twitter or Facebook, is one solution, but scientist are few to do so for the moment.
It is also crucial that we meet the clinicians to get a better understanding of the disease as a whole because that will help us to ask the most relevant scientific questions.
Do you know Synodos, the research consortium on NF2 driven Children's Tumor Foundation? What do you think of this project?
I think Synodos is a good initiative to structure the research on NF2 in a kind of consortium. It will provide funding to several groups and that is essential. However, Synodos doesn't concern all the groups working on NF2. Several labs that are strongly involved in NF2 research are not concerned by Synodos. I understand that, with limited resources, it is important not to fractionate them too much. However, the NF2 community is small and the risk is that it will become smaller is NF2 labs don't get support. In a sense, we need several Synodos.
What do you think can provide the patients groups in terms of research?
Patients groups are important for research. They certainly help to structure research on NF2 (and NF in general). This can be achieved by organizing meetings, raising funds, increasing awareness in the public opinion, lobbying etc... My experience is that meeting with patients, communicating with them improves my research. I get a better sense of what should be priorities in research on NF2 and helps me to interact better with clinicians. There is obviously a privileged relationship between patients and clinicians which is normal. I think it is important that research scientist join in a kind of "menage a trois", as we say. It is important that patients know what research can and cannot do for them. But is is important that scientist understand what is NF2 from the patient point of view. So, patient groups can really help in this context I think. In addition, and not surprisingly, raising money to help research is also an important point.
In one of your recent tweets, you said that studying how merlin affects breast cancer at some point is more simple and efficient than in schwannomas and meningiomas. Can you detail more this idea?
It is likely that many of the molecular process in which merlin is involved are conserved between the different tissues and cells of the human body. It is of course certainly more relevant to study these processes in Schwann or Meningeal cells since they relate directly to the NF2 disease. But these types of cells are tricky to obtain and manipulate and make the research more difficult. The field of research on breast cancer is much more developed than NF2 field of research. For example, there are dozens of cellular models of breast cancers as opposed to a couple Schwannoma cell lines. Furthermore, these breast cells are much better characterized genetically and very diverse. The models of breast tumors xenografts are very common, very well characterized and easy to manipulate. Xenografts models for schwannomas and meningiomas are almost non existent. So, exploring merlin functions in the context of breast cancer allows easier and more in depth analysis to be done. Using breast cancer as a model, we have recently identified important function of merlin in breast tumor progression, that is to say how a benign tumor becomes more aggressive. These mechanisms we think could be very important to study meningiomas, because meningiomas also progress from a benign stage to a more aggressive one. So, by doing some research on merlin in breast cancer, we can learn about NF2 disease.
How much money is needed to fund research aimed at finding a treatment or cure for NF2?
Certainly, a lot. Doing research is expensive, requires many people and equipment and is a long lasting process. I take an example. A typical research project developed here in France, that would require one person (a post doc), for a duration of three years (a typical project duration), reagents and equipment can be estimated to cost about 200 000 euros. A large part is salary, but this also includes reagents and other resources needed for the project. And the NF2 community needs many of them to improve treatments, test new ones and find a cure. It is not easy to get this amount from one unique source. We need to combine several grants to make projects feasible. I was awarded smaller grants from the French NF foundation but that money was very important for the development of the project that we recently published although it did not cover all of our expanses. Importantly, in term of funding, what is important is continuity so that the research effort is permanent, so that the people working on NF2 can stay in the field. I was referring above to some of our studies on breast cancer. This was also a way for us to apply for resources from a different field of cancer research in order to secure continuity in our funding. Working on NF2 is difficult because dedicated funding sources are few.
What is considered neccesary for NF2 research be encouraged?
I think that all aspects of the NF2 research need to be encouraged. The NF2 community is small and what is important is that new students, post doc and scientist join the effort.
I would say, but this is a personal opinion, that new NF2 tumor models are needed and I think that an effort on developing xenografts models is important for the future. It is also important to generate more cell lines from human tumors. These models are very difficult to generate and require dedicated peoples to develop. NF2 field certainly requires the development of large and well characterized tumor banks that are accessible to researchers. This is a absolute necessity and these banks have been developed for all major types of cancers and they proved to be crucial for research. But again, doing so is time and money consuming. Finally, initiatives that promote collaboration between groups, especially here in Europe, are important and should be encouraged.
How do you see the development of research in the short, medium and long term?
In the short term, from my perspective, several discoveries that have been made during the last 5-10 years concerning the mechanisms of tumor growth regulated by merlin are likely to be evaluated for their clinical potential. More specifically, drugs that target certain types of receptors like Her3, PDGFR for example. These drugs already exist and could be tested in the short term.
A new target was identified few years ago and could become a therapeutic target, the hippo pathway, which is very interesting. This pathway, interestingly, is also involved in other types of cancers (breast or colon cancer but also lung tumors). In a sense, it is a good new for NF2 because developing new drugs against frequent cancers is more likely to be of interest for pharma companies and these drugs could be of benefit to NF2 patients. So I think that the field of research and drug development about Hippo is something to follow during the coming years. In the medium term also, if we succeed in developing better cellular models, screening strategies that allow to test thousands of molecules or explore the entire human genome should provide a wealth of information on the mechanisms that sustain tumor growth and which class of molecules could block it. So, large scale genomic or pharmacologic studies are likely to emerge in the NF2 field. These types of studies will certainly have an impact on another important issue which is the origin of variability of the disease between the patients. Why some tumors grow and some don't, why some patients respond to treatment and other don't. The same treatment doesn't fit all patients and it is important to understand why, so that the future treatments can be adapted to the patients. The long term, for research is by definition unpredictable. I cannot tell which discovery will be made that would change the way patients will be treated in the future. These discoveries may come from other areas of research. It could concern stem cell research, new ways to locally deliver drugs to maximize the effect on tumors, who knows. But it is clear that sustained effort to better understand how the NF2 tumors develop will provide new and better ideas of treatment in the long term.
Interview: Florencia Sarratea