M. Poirot / S. Silvente-Poirot

  Cholesterol metabolism and therapeutic innovations

 

 

 

 

 

 

 

 

 

Our research project at a glance

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.

 

 

Objectives

We want to identify and validate new therapeutic targets, to identify new mechanisms of resistance to treatments and to improve outcome through a better stratification of cancers.

Specifically, we are studying the contribution of cholesterol metabolism in the response to the endocrine therapy with Tamoxifen (Tam) and aromatase inhibitors (AI).  We identified a new metabolic pathway centered on cholesterol-5,6-epoxide hydrolase (ChEH). ChEH controls cholesterol-5,6-epoxide (5,6-EC) metabolism and is a direct target of Tam (de Medina et al, PNAS 2010). We showed its importance in the anticancer action of Tam. ChEH controls the production of metabolites with opposite properties in cancers.

We have first identified dendrogenin A (DDA), an amino-oxysterol tumor suppressor produced by healthy tissues (de Medina et al, Nat Commun 2013). Recently we discovered an onco-metabolite tumor promoter produced by cancer cells. The identification of these two end-products of the cholesterol metabolism with opposite properties opens up new perspectives for the development of novel therapies. It will help to understand fine mechanisms involved in acquired and intrinsic resistances to various therapies (Silvente-Poirot & Poirot, Science 2014).  

Our objectives are :

  • to characterize the molecular actors controlling this metabolic pathway,
  • to elucidate the mechanism of action of these new metabolites, including their impact on exosome production and phenotypes,
  • to characterize their impact on the tumor microenvironment (in particular on the immune system).

Our objectives are also to propose innovative therapeutic approaches to counter or circumvent resistances to therapy and to identify new surrogate biomarkers of responses.

 

Our approach links basic research to medical applications with a goal of valorization in partnership with our spin off, Affichem (9 patents filed over the last 5 years).

 

Key words

 

  • Tamoxifen
  • SERM
  • Oxysterols
  • Cholesterol biosynthesis
  • Cholesterol metabolism
  • Dendrogenin
  • Cholesterol-5,6-epoxide hydrolase
  • Cholesteryl esters
  • Nuclear receptors
  • Enzymology
  • Medicinal chemistry
  • LC/MS
  • Radiolabeling
  • Cell differentiation
  • Cell death
  • Autophagy
  • Immune system
  • Tumor suppressor
  • Tumor promoter
  • Exosomes
  • Imaging

 

Selected publications


2017

Leignadier, J; Dalenc, F; Poirot, M; Silvente-Poirot, S

Improving the efficacy of hormone therapy in breast cancer: The role of cholesterol metabolism in SERM-mediated autophagy, cell differentiation and death Journal Article

Biochem Pharmacol, 144 , pp. 18-28, 2017, ISSN: 1873-2968 (Electronic) 0006-2952 (Linking).

Links | BibTeX

Maud Voisin Philippe de Medina, Arnaud Mallinger Florence Dalenc Emilie Huc-Claustre Julie Leignadier Nizar Serhan Regis Soules Grégory Ségala Aurélie Mougel Emmanuel Noguer Loubna Mhamdi Elodie Bacquié Luigi Iuliano Chiara Zerbinati Magali Lacroix-Triki Léonor Chaltiel Thomas Filleron Vincent Cavaillès Talal Al Saati Philippe Rochaix Raphaelle Duprez-Paumier Camille Franchet Laetitia Ligat Frederic Lopez Michel Record Marc Poirot ; Silvente-Poirot., Sandrine

Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor Journal Article

Proc Natl Acad Sci U S A, in press , 2017.

Links | BibTeX

Soules, R; Noguer, E; Iuliano, L; Zerbinati, C; Leignadier, J; Rives, A; de Medina, P; Silvente-Poirot, S; Poirot, M

Improvement of 5,6alpha-epoxycholesterol, 5,6beta-epoxycholesterol, cholestane-3beta,5alpha,6beta-triol and 6-oxo-cholestan-3beta,5alpha-diol recovery for quantification by GC/MS Journal Article

Chem Phys Lipids, 207 (Pt B), pp. 92-98, 2017, ISSN: 1873-2941 (Electronic) 0009-3084 (Linking).

Links | BibTeX

2016

Silvente-Poirot, S; de Medina, P; Record, M; Poirot, M

From tamoxifen to dendrogenin A: The discovery of a mammalian tumor suppressor and cholesterol metabolite Journal Article

Biochimie, 130 , pp. 109-114, 2016, ISSN: 1638-6183 (Electronic) 0300-9084 (Linking).

Links | BibTeX

2014

Silvente-Poirot, S; Poirot, M

Cancer. Cholesterol and cancer, in the balance Journal Article

Science, 343 (6178), pp. 1445-6, 2014, ISSN: 1095-9203 (Electronic) 0036-8075 (Linking).

Links | BibTeX

2013

de Medina, P; Paillasse, M R; Segala, G; Voisin, M; Mhamdi, L; Dalenc, F; Lacroix-Triki, M; Filleron, T; Pont, F; Saati, T A; Morisseau, C; Hammock, B D; Silvente-Poirot, S; Poirot, M

Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties Journal Article

Nat Commun, 4 , pp. 1840, 2013, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).

Links | BibTeX

2012

Silvente-Poirot, S; Poirot, M

Cholesterol epoxide hydrolase and cancer Journal Article

Curr Opin Pharmacol, 12 (6), pp. 696-703, 2012, ISSN: 1471-4973 (Electronic) 1471-4892 (Linking).

Links | BibTeX

2011

Record, M; Subra, C; Silvente-Poirot, S; Poirot, M

Exosomes as intercellular signalosomes and pharmacological effectors Journal Article

Biochem Pharmacol, 81 (10), pp. 1171-82, 2011, ISSN: 1873-2968 (Electronic) 0006-2952 (Linking).

Links | BibTeX

2010

de Medina, P; Paillasse, M R; Segala, G; Poirot, M; Silvente-Poirot, S

Identification and pharmacological characterization of cholesterol-5,6-epoxide hydrolase as a target for tamoxifen and AEBS ligands Journal Article

Proc Natl Acad Sci U S A, 107 (30), pp. 13520-5, 2010, ISSN: 1091-6490 (Electronic) 0027-8424 (Linking).

Links | BibTeX

2009

de Medina, P; Paillasse, M R; Payre, B; Silvente-Poirot, S; Poirot, M

Synthesis of new alkylaminooxysterols with potent cell differentiating activities: identification of leads for the treatment of cancer and neurodegenerative diseases Journal Article

J Med Chem, 52 (23), pp. 7765-77, 2009, ISSN: 1520-4804 (Electronic) 0022-2623 (Linking).

Links | BibTeX