Even during his studies, Marc Poirot was fascinated by the connection between biology and chemistry, two previously separate disciplines. The head of research comes from this marriage Insert pulled the strings on new pathways of cholesterol conversion and their effects on breast cancer. A work that was recently awarded the Schroepfer PrizeAmerican Society of Oil Chemists.
An article that can be found in the magazine Inserm No. 58
Ask researchers when their interest in science began and almost all of them will answer: “Since childhood!” » Marc Poirot is one of them. “ I was initially interested in biology, I observed nature a lot and always had an encyclopedia to hand to find answers to my questions. “, he remembers. Five decades later, the researcher still carries this passion deep in his body: every day in his team’s premises at the Cancéropôle site in Toulouse, he tries to understand this nature that fascinated him from a young age, now in Its aspects are most advanced: cholesterol metabolism and the effects of its deregulation in breast cancer.
Before he arrived there, the scientist’s training path was marked by crucial encounters. The one with his philosophy professor Olivier Schwartz, who convinced him to turn to experimental sciences. Then with organic chemistry, which gave him the opportunity to create tailor-made molecules. Then with Jean Asselineau, the former laboratory director at the CNRS, who encouraged him to enroll in a new doctoral program combining chemistry and biology, while previously it was impossible to take a course that combined the two disciplines, which led the young student to do so forced to juggle between the schedules of two master’s degrees. Eventually he meets Sandrine Silvente while waiting in line to register at the university. “ It was love at first sight and we never left each other » he says about the woman who would become his wife and with whom he later founded the Cholesterol Metabolism and Therapeutic Innovations team.
To identify a target for tamoxifen…
When he started working in the German chemical industry, a chemistry professor, Jean-Jacques Périé, informed him about the creation of a DEA in the chemistry of biomolecules: there was no question of missing this revolution that the scientist had expected from the beginning his studies, the “marriage” of biology and chemistry! That’s why Marc Poirot wrote a thesis with Jean-Charles Faye, chemical engineer and researcher at Inserm. “ There I developed chemical tools and identified AEBS (English acronym for “Antibodies Binding Site”).estrogen“), which is a pharmacological target of a drug used to treat hormone-dependent breast cancer, tamoxifen », he remembers. At a time when campuses are disconnected, Marc Poirot exhausts universities’ bibliographic resources to expand his knowledge of chemistry and biochemistry. There he discovered the existence of steroid alkaloids, substances that were then considered excluded from the animal kingdom but that had special physicochemical properties and were often bioactive in humans. “ To my knowledge, no one had studied their existence in mammals », he remembers these cholesterol derivatives, which will be the focus of his research.
After a postdoctoral position at Sanofi, where he continued the characterization of the AEBS site, followed by a position as research manager at Inserm in the team of his mentor Jean-Charles Faye, Marc Poirot joined National Institutes of Health, in Bethesda, USA, where he works on steroid hormone receptors. A convergence occurs between his research topics and those of his wife Sandrine Silvente-Poirot, CNRS researcher in biochemistry and molecular pharmacology, and they join forces to form a transdisciplinary research team at the Toulouse Purpan Pathophysiology Center.
…to new therapeutic approaches
The focus of her work: cholesterol derivatives and their tumor-promoting and suppressing effects. The researcher and his team first highlighted the previously unimagined importance of cholesterol for the anti-cancer effect of tamoxifen. They also showed that there was an audience on the AEBS website that this cancer drug was targeting. an enzyme called cholesterol 5,6-epoxide hydrolase (ChEH), crucial for the biochemical conversion of cholesterol. These observations lead scientists to suspect that there may be an as-yet-unknown pathway for cholesterol conversion. To test this hypothesis, they synthesized cholesterol derivatives using natural amines such as histamine or polyamines. These derivatives, which they later called “dendrogenins,” are steroid alkaloids. “ These dendrogenins were found to be able to induce the differentiation of undifferentiated or dedifferentiated cells, which was of interest to our cancer research since tumor cells are characterized by the loss of their differentiation state. We then looked for them and found them in mammalian tissues, proving the existence of bioactive steroid alkaloids in humans. », summarizes the researcher. Among these molecules, dendrogenin A (DDA) exhibits notable anticancer properties. However, researchers are observing this Cancer cells have lost the ability to produce DDA ! “ Sandrine showed that instead of this molecule, they produce an oncometabolite that we called “oncosterone,” which promotes the development of breast tumors. “, he continues. So many successive discoveries that reveal new possibilities for cancer treatments, over an effect on cellular mechanisms not previously targeted by conventional treatments.
From the study of the tamoxifen binding site to these conclusions and their therapeutic significance, the path traveled appears to be dizzying. “ It is the case!confirms Marc Poirot. At first we feel overwhelmed by the tasks to be completed. Only in retrospect do we realize the extent of the work done, and successfully! » The researcher who won the renowned Schroepfer PrizeSociety of American Oil Chemists, an American professional society interested in lipids in all their applications, appreciates all efforts made. “ It is a great honor for me and my teamhe recognizes. This award is a clear encouragement to continue our work in exploring this new metabolic pathway, which still promises us great discoveries. »
Marc Poirot and Sandrine Silvente-Poirot lead the team together Cholesterol metabolism and Therapeutic innovations at the Toulouse Cancer Research Center (Unit 1037 Inserm/Université Toulouse III – Paul-Sabatier).
Author: AB
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