Since his studies, Marc Poirot has been captivated by the union of biology and chemistry, two disciplines which had previously been compartmentalised. From this marriage, the Inserm research director has studied new cholesterol transformation pathways and their involvement in breast cancer. This research was recently awarded the American Oil Chemists’ Society Schroepfer Medal.
Ask researchers when their wonder for science began and most will say ‘in childhood!’ And Marc Poirot is one of them. « I was attracted to biology first and spent a lot of time observing nature with the help of an encyclopaedia to find answers to my questions », he remembers. Five decades later, this passion remains undimmed. Every day, he and his team at the Cancéropôle site in Toulouse try to understand this very nature that has fascinated him for so long, but this time in its most cutting-edge aspects: cholesterol metabolism and the effects of its deregulation in breast cancer.
Before reaching that point, the scientist’s training was punctuated with decisive encounters. For example, with his philosophy professor Olivier Schwartz, who convinced him to focus on the experimental sciences. And with organic chemistry, through which he discovered the possibility of creating custom molecules. Then with Jean Asselineau, former laboratory director at the CNRS, who encouraged him to enrol in a new doctoral course combining chemistry and biology – when previously a course combining the two disciplines was impossible, obliging the young student to juggle two master’s degrees. And finally with Sandrine Silvente in the queue to enrol at university. « It was love at first sight and we have been together ever since », he says about the woman who went on to become his wife and co-founder of the Cholesterol Metabolism and Therapeutic Innovations team.
From the identification of a tamoxifen target…
As he began working in the German chemical industry, Poirot was informed by chemistry professor Jean-Jacques Périé of the creation of a post-graduate diploma (DEA) in biomolecular chemistry: there was no question of missing out on this revolution that he had anticipated since the beginning of his studies – the ‘marriage’ between biology and chemistry! So Poirot embarked on a thesis supervised by Jean-Charles Faye, a chemical engineer and researcher at Inserm. « There I developed chemical tools and identified AEBS (antiestrogen binding site), which is a pharmacological target of tamoxifen – a drug used to treat hormone-dependent breast cancers », he explains. At a time when campuses were not connected, Poirot exhausted academic bibliographic resources in expanding his knowledge of chemistry and biochemistry. He discovered the existence of steroidal alkaloids, substances at the time thought to be excluded from the animal kingdom but possessing specific physical-chemical properties and often bioactive in humans. « To my knowledge, nobody had researched their existence in mammals », he recalls regarding these cholesterol derivatives, which were to become central to his research.
After a post-doctoral fellowship at Sanofi where he continued to characterise the AEBS site, followed by a research fellowship at Inserm in the team of his mentor Jean-Charles Faye, Poirot joined the National Institutes of Health in Bethesda, USA, where he worked on steroid hormone receptors. With his research themes becoming more closely linked with those of his wife, CNRS biochemistry and molecular pharmacology researcher Sandrine Silvente-Poirot, they joined forces to create a transdisciplinary research team at the Toulouse Purpan Pathophysiology Centre.
... to that of new therapeutic avenues
At the heart of their research: cholesterol derivatives and their tumour-promoting and suppressant effects. The researcher and his team began by highlighting the hitherto unsuspected importance of cholesterol in the anticancer action of tamoxifen. They also demonstrated the existence, at the AEBS site (targeted by this cancer drug), of an enzyme called cholesterol‑5,6‑epoxide hydrolase (ChEH), which plays a crucial role in the biochemical transformation of cholesterol. These observations lead the scientists to think that there is an as yet unknown pathway for cholesterol transformation. To test this hypothesis, they synthesised cholesterol derivatives using natural amines, such as histamine or polyamines. These derivatives, which they later called « dendrogenins », are steroidal alkaloids. « These dendrogenins have been shown to induce the differentiation of undifferentiated or dedifferentiated cells, which has echoed our research on cancer because tumour cells are characterised by the loss of their state of differentiation. We then searched for and found them in mammalian tissues, thereby proving the existence of bioactive steroidal alkaloids in humans », summarises the researcher. Among these molecules, dendrogenin A (DDA) shows remarkable anticancer properties. However, the researchers have observed that cancer cells have lost the ability to produce DDA! « Sandrine has demonstrated that instead of this molecule, they produce an oncometabolite, which we have called « oncosterone », that promotes breast tumour development », he continues. With this succession of discoveries, new possibilities for cancer treatments are emerging, via an action on cell mechanisms not previously targeted by conventional treatments.
From the study of the tamoxifen binding site to these conclusions and their therapeutic significance, the progress made appears dizzying. « And it is! confirms Poirot. At first you feel overwhelmed by everything you have to do. It is with hindsight that you realise the extent of the work accomplished, which on top of that is successful! » The researcher, who in May was awarded the prestigious Schroepfer Medal by the American Oil Chemists’ Society, a US learned society focused on lipids in all their fields of application, is all the more appreciative of the efforts made. « It is a great honour for me and my team, he acknowledges. This award is a clear encouragement to continue our work to explore this new metabolic pathway, which continues to promise great discoveries. »
Marc Poirot and Sandrine Silvente-Poirot co-lead the Cholesterol Metabolism and Therapeutic Innovations team at the Toulouse Cancer Research Centre (unit 1037 Inserm/Toulouse III – Paul-Sabatier University).
Author : A. B.