Team 12: (M.Poirot, S. Silvente-Poirot): to study the role of cholesterol metabolism in cancer progression and control.
Our team has a long expertise in the metabolism of cholesterol, oxysterols and lipids, in the pharmacology of nuclear and membranous receptors as well as in the study of enzymes.
Currently, we are studying the role of cholesterol metabolism in the control or progression of cancers and in resistance to therapies, with a particular focus in breast cancer. Our team is composed of scientists with different and complementary skills (chemistry, biochemistry, pharmacology, immunology) and medical doctors who make possible to transpose basic science discoveries from the laboratory into new therapeutic strategies in the clinic along with partnerships with the industry to fight cancer. Medicinal chemistry and technology development are important goals of our team and we are particularly interested in developing new probes for the molecular imaging of tumors. We already have produced many new compounds and technologies associated with filled patents.
Breast cancer (BC) is the most common female cancer. It affects more than 1 million women worldwide and approximately 500,000 patients die each year from this disease. Recently, cholesterol metabolism has been implicated not only in the development of BC, but also in the resistance to tamoxifen (Tam). Tam remains a major treatment of BC and in the U.S. it is also proposed to prevent them.
Our team identified an important high affinity target of Tam involved in this metabolism, the cholesterol-5,6-epoxide hydrolase (ChEH) (de Medina P. et al, 2010, PNAS), which could participate not only in tumor progression but also in BC resistance to Tam (Poirot M. et al, 2012 Curr Opinion in Pharmacol). Accordingly, DHCR7 overexpression (one of the enzymes forming the ChEH) is predictive of BC Tam-resistance (Silvente-Poirot et al, 2012, Curr Opinion in Pharmacol.). Moreover, in the team, we demonstrated that in normal breast tissue this metabolic pathway generates via an enzymatic process a tumor suppressor metabolite inducing the differentiation and death of tumor cells, that we called Dendrogenin A (DDA). DDA is a new class of sterol and the first steroidal alkaloid identified to date in mammal. In contrast, we found lower levels of DDA in tumor cells and breast cancers, suggesting a deregulation of DDA biosynthesis during carcinogenesis (de Medina et al, 2013, Nat Commun, Dalenc et al, 2015, Curr Med Chem). Thus, we identified a metabolic balance between healthy tissue and tumor that we discussed in a recent perspective in Science (Silvente-Poirot S. et Poirot M. 2014).
Figure 1: DDA is a natural cholesterol metabolite found in mammals with anti-tumor properties.
DDA level was strongly decreased in BC tumors. Administration of low doses of DDA into mice induced a drastic inhibition of tumor growth and improved mice survival indicating that DDA could be a drug candidate for cancer treatment (de Medina et al, Nat Commun, 2013, Dalenc et al, Curr Med Chem, 2015). Deregulations along the cholesterol metabolic pathway may be detrimental to the formation of metabolites that are beneficial to cell integrity and differentiation (such as DDA) and may favor the accumulation of metabolites with tumor promoting activity (such as 27HC) (Silvente-Poirot S and Poirot M., Science, 2014).
Currently, our objectives are to characterize the molecular actors involved in this metabolic pathway and their mechanism of action, to study their deregulations in cancers and their role in the physiopathology of cancers and in resistance to therapy.
Our aims are to propose innovative therapeutic approaches for breast cancer resistance and other cancers, to identify new non-invasive biomarkers for predicting response or resistance to therapies as well as to identify early cancer biomarkers for risk prediction and early detection of cancer.
Marc Poirot & Sandrine Silvente-Poirot's team is part of PHUC CAPTOR