title: SAR405838: A Novel and Potent Inhibitor of the MDM2:p53 Axis for the Treatment of Dedifferentiated Liposarcoma.
abstract: OBJECTIVE
  Dedifferentiated liposarcoma (DDLPS) is an aggressive malignancy that can recur locally or disseminate even after multidisciplinary care. Genetically amplified and expressed MDM2, often referred to as a "hallmark" of DDLPS, mostly sustains a wild-type p53 genotype, substantiating the MDM2:p53 axis as a potential therapeutic target for DDLPS. Here, we report on the preclinical effects of SAR405838, a novel and highly selective MDM2 small-molecule inhibitor, in both in vitro and in vivo DDLPS models.
  
  
  METHODS
  The therapeutic effectiveness of SAR405838 was compared with the known MDM2 antagonists Nutlin-3a and MI-219. The effects of MDM2 inhibition were assessed in both in vitro and in vivo. In vitro and in vivo microarray analyses were performed to assess differentially expressed genes induced by SAR405838, as well as the pathways that these modulated genes enriched.
  
  
  RESULTS
  SAR405838 effectively stabilized p53 and activated the p53 pathway, resulting in abrogated cellular proliferation, cell-cycle arrest, and apoptosis. Similar results were observed with Nutlin-3a and MI-219; however, significantly higher concentrations were required. In vitro effectiveness of SAR405838 activity was recapitulated in DDLPS xenograft models where significant decreases in tumorigenicity were observed. Microarray analyses revealed genes enriching the p53 signaling pathway as well as genomic stability and DNA damage following SAR405838 treatment.
  
  
  CONCLUSIONS
  SAR405838 is currently in early-phase clinical trials for a number of malignancies, including sarcoma, and our in vitro and in vivo results support its use as a potential therapeutic strategy for the treatment of DDLPS.
authors.affiliation: The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences, Houston, Texas. Department of Surgical Oncology, Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio.
authors.forename: Kate Lynn J
authors.initials: KL
authors.lastname: Bill
authors.affiliation: The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Garnett
authors.affiliation: Sanofi Oncology, Vitry-sur-Seine, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meaux
authors.affiliation: The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: XiaoYen
authors.initials: X
authors.lastname: Ma
authors.affiliation: The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bolshakov
authors.affiliation: Sanofi Oncology, Vitry-sur-Seine, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Barriere
authors.affiliation: Sanofi Oncology, Vitry-sur-Seine, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Debussche
authors.affiliation: The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Surgical Oncology, Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio.
authors.forename: Bethany C
authors.initials: BC
authors.lastname: Prudner
authors.affiliation: Department of Surgical Oncology, Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio.
authors.forename: Lucia
authors.initials: L
authors.lastname: Casadei
authors.affiliation: Department of Surgical Oncology, Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio.
authors.forename: Danielle
authors.initials: D
authors.lastname: Braggio
authors.affiliation: Department of Surgical Oncology, Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Lopez
authors.affiliation: Department of Surgical Oncology, Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio.
authors.forename: Abbie
authors.initials: A
authors.lastname: Zewdu
authors.affiliation: Department of Surgical Oncology, Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio.
authors.forename: Hemant
authors.initials: H
authors.lastname: Bid
authors.affiliation: Department of Surgery, The Sheba Medical Center, Tel Aviv, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
authors.affiliation: The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Surgical Oncology, Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Raphael.Pollock@osumc.edu.
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage*; D008080:Liposarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D046228:Microarray Analysis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013141:Spiro Compounds / Q000008:administration & dosage*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007093:Imidazoles; D007211:Indoles; C574930:MI-219; D010879:Piperazines; D013141:Spiro Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C000593797:SAR405838; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2