Better diagnosis, innovative treatments, the research into childhood cancers by Olivier Delattre – a full-time researcher but a pediatrician at heart – has paid off. His insatiable curiosity and tenacity in unraveling the mysteries of these diseases have earned him the Grand Prize.
Once a pediatrician, always a pediatrician
« Back when I was choosing what to study for my higher education, many fields attracted me, such as science, justice, social relations and injustice, humans, and interpersonal relationships. Medicine seemed a good compromise, enabling me to make the most of all my areas of interest, » explains Olivier Delattre, director of the Inserm Cancer, heterogeneity, instability and plasticity unit at Institut Curie in Paris (unit 830 Inserm/Institut Curie). In 1975, he began his medical studies that led to a pediatrics residency, « somewhat by chance, he acknowledges. But one that I quickly came to love. » In 1982, he did the civil equivalent to military service at the Principal Hospital of Dakar in Senegal. Although he did not know it at the time, this experience was to lay the foundations for his future career. « My year there was such a learning experience. There was a very enriching social aspect to the work and we were caring for children, which is very rewarding, he describes. Nevertheless, half the children I saw would go on to die, either from malnutrition or infectious diseases due to the lack of vaccines. I told myself that we doctors are at the end of the chain and that the solution is upstream. »
Despite this, Delattre continued his residency, particularly in the Pediatric Oncology Department of Institut Curie. « It was then that I read a publication written by Inserm doctor and researcher Jean-Paul Lévy concerning oncogenes, which are genes involved in cancers, he remembers. I was fascinated and told myself that finally there’s an avenue for improving our understanding and treatment of cancer. That was what I wanted to work on! » No sooner said than done: the pediatrician took leave from his residency to do the equivalent of a two-year master’s in biology. He spent the first year in Gilles Thomas’ laboratory at Institut Curie, and the second with Richard Breathnach’s team at the Pierre Chambon laboratory at the Institute of Biological Chemistry of the Strasbourg Faculty of Medicine. To finish, he joined James Gusella for a few months at the Massachusetts General Hospital in Boston, USA. Although his interest in oncology research deepened, he still had difficulty choosing between a career as a pediatrician or as a researcher.
Pediatrician by day, researcher by night
He resumed his residency at Institut Curie and began a biology dissertation in Gilles Thomas’s laboratory. « For two years, I was a pediatrician by day and a researcher by night... » Despite the workload, Delattre obtained his doctorate of medicine in 1990 and his doctorate of science the year after. But such a pace could not continue. Something had to give. It was now time to make a decision between treating young patients and researching treatments on their behalf.
He chose the second option, with the scales tipped by Inserm following his success in a competitive examination in 1991. « Two points attracted me to Inserm. Its interdisciplinarity and the freedom given to its researchers. We are free to develop projects as long as they are evaluated properly. And our roles are national ones, so we have the possibility to relocate, which was and still is very important to me, although it is not something that I’ve made that much use of because I’m still at Institut Curie... » Delattre was therefore a researcher, but according to the old adage of « once a pediatrician, always a pediatrician » he chose to study childhood cancers, still as part of Gilles Thomas’ team. « From the human point of view, these cancers are a real injustice! he says. And scientifically their study is made relatively easy due to the fact that they are genetically stable and thereby constitute ‘simplified tumor models’ in adults. »
A long-term investigation
In 1992, he was involved in a world first. His team identified and characterized the genes rearranged by translocation – an exchange of genetic material between two chromosomes – responsible for Ewing’s sarcoma, a form of bone cancer that occurs in children and young adults. In the wake of this, the team showed that the Ewing Sarcoma – Friend Leukemia Integration (EWS-FLI) protein generated from this rearrangementpromotes the expression of genes involved in abnormal cell proliferation. « I was naive back then. I used to tell myself that because we knew the gene, we would understand the function of the protein it codes, and we could inhibit it to treat that cancer,he acknowledges. Thirty years later, we have made a lot of progress but still do not have a specific treatment... » Which is not surprising: « The cell always finds a way to evade it, he continues. However, the guilty protein does not work alone. We – and other teams around the world – are trying to target its accomplices. » Thus in 2022, Delattre’s team observed that EWS-FLI induces the expression of peptidespresent only in sarcoma cells. If this « protein signature » is confirmed, targeted immunotherapy could be envisaged so thatthe patient’s immune systemeliminates these tumor cells. In terms of diagnosis, the impact of the initial research on this sarcoma was more immediate, with the « genetic signature » paving the way for early diagnosis and better follow-up of this disease. To meet this expectation on the part of physicians, « it was imperative to have standardized diagnostic protocols, which was incompatible with our research activity, » emphasizes the researcher. So I transferred our know-how for a clinical application and created in 1995, for the hospital sector of Institut Curie, the first somatic genetics unit in France. »
A cascade of discoveries
The year 1995 also marked a new turning point in his career. While Gilles Thomas moved to the Human Polymorphism Study Center (CEPH) at Saint-Louis Hospital in Paris, Delattre chose to set up his own team at Institut Curie, which received Inserm accreditation in 1998. Together with Alain Aurias, who also remained at Institut Curie, he focused his attention on rhabdoid tumors. These rare but very aggressive cancers are heterogeneous. They can affect the kidneys and central nervous system, as well as the liver and the bones. The two researchers identified the common denominator: the cells of these tumors had lost the SMARCB1 gene that encodes one of the proteins in a specific protein complex. Normally, this complex finely regulates the expression of a set of genes which, thus coordinated, have a tumor suppressant effect. The other side of the coin is that when one of the proteins in the complex is absent or abnormal, this regulation is damaged, which promotes the development of cancer. This identification first of all improved the diagnosis of rhabdoid tumors in children, and then triggered an avalanche of discoveries. « We now know that alterations of this complex are observed in nearly 20% of pediatric and adult cancers, » says Delattre. In addition, some are associated with the hyperactivity of a protein, EZH2, which promotes abnormal cell proliferation. This knowledge has led to the development of an EZH2 inhibitor, tazemetostat, developed by the company EpiZyme, which is currently being evaluated in patients, both children and adults, for different forms of cancer. In parallel, Delattre’s team was also focused on neuroblastoma, the particularity of which could only elicit the researcher’s curiosity. « This malignant extracranial solid tumor that affects young children behaves in a fascinating way. In some cases, it is very aggressive and resists treatment, whereas in others it resolves spontaneously, he explains. We have shown that one of the causes of this difference in outcome is due to the presence or absence of anaplastic lymphoma kinase (ALK) protein mutations located on the tumor cell membrane. » Its mutated version pushes cells to constantly proliferate. And once again, this research has had two major impacts: the predictive-value diagnosis of tumor progression, and potential treatments. In this regard, several medicines are currently being evaluated worldwide.
Within three decades, Delattre, « together with the unit’s other pediatric oncology teams, representing some fifty researchers and physician-researchers, » has made a major contribution to improving the knowledge of childhood cancers. But perhaps what best defines his career is the SIREDO center (for Care, Innovation & Research in Childhood, Adolescent & Young-Adult Oncology) that he founded in 2018 and has been leading ever since. « Within the same entity we have brought together the healthcare and research teams from Institut Curie, dedicated to solid tumors affecting the under-25s, » he described. The idea is that the teams get to know each other, share areas for reflection and develop shared projects, the objective being for young patients to benefit from very basic research as quickly as possible. » This desire to help provide even better treatment to a larger number of patients has always motivated Delattre and is the reason why he has been selected for the Grand Prize. « I am very proud and honored to receive this recognition from Inserm, highlights the researcher whose curiosity remains unabated. Cancer is a strange biological object. It is observed in virtually the entire animal and plant kingdom, and is a common disease in humans. However, at the cellular level, it is an extremely rare phenomenon: out of the billion cells that make up an individual, only one becomes cancerous despite having a variety of mechanisms for achieving this. There is a paradox between multiplicity and scarcity that as a researcher I continue to ponder. »