title: Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na.
abstract: BACKGROUND
  We previously demonstrated upregulation of c-myc, survivin, and cyclin D1 in CD34+ bone marrow mononuclear cells (BMMNCs) of patients with trisomy 8 and monosomy 7 myelodysplastic syndromes (MDS). "Knockdown" of cyclin D1 by RNA interference decreased trisomy 8 cell growth, suggesting that this might be a therapeutic target in MDS.
  
  
  METHODS
  We performed preclinical studies using BMMNCs from patients with MDS and AML to examine the effects of the styryl sulfone ON 01910.Na on cyclin D1 accumulation, aneuploidy, and CD34+ blast percentage. We next treated twelve patients with higher risk MDS and two trisomy 8 AML patients with ON 01910.Na on a phase I clinical protocol (NCT00533416).
  
  
  RESULTS
  ON 01910.Na inhibited cyclin D1 expression, and was selectively toxic to trisomy 8 cells in vitro. Flow cytometry studies demonstrated increased mature CD15+ myeloid cells and decreased CD34+ blasts. Three patients treated with ON 01910.Na on a clinical had decreased bone marrow blasts by ≥ 50%, and three patients had hematologic improvements, one of which was sustained for 33 months. Patients with hematologic responses to ON 01910.Na had decreased cyclin D1 expression in their CD34+ cells.
  
  
  CONCLUSIONS
  The preclinical results and responses of patients on a clinical trial warrant further investigation of ON 01910.Na as a potential novel targeted therapy for higher risk MDS patients.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. olnesmj@nhlbi.nih.gov
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Olnes
authors.forename: Aarthie
authors.initials: A
authors.lastname: Shenoy
authors.forename: Barbara
authors.initials: B
authors.lastname: Weinstein
authors.forename: Loretta
authors.initials: L
authors.lastname: Pfannes
authors.forename: Kelsey
authors.initials: K
authors.lastname: Loeliger
authors.forename: Zachary
authors.initials: Z
authors.lastname: Tucker
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.forename: Minjung
authors.initials: M
authors.lastname: Kwak
authors.forename: Francois
authors.initials: F
authors.lastname: Wilhelm
authors.forename: Agnes S M
authors.initials: AS
authors.lastname: Yong
authors.forename: Irina
authors.initials: I
authors.lastname: Maric
authors.forename: Manoj
authors.initials: M
authors.lastname: Maniar
authors.forename: Phillip
authors.initials: P
authors.lastname: Scheinberg
authors.forename: Jerome
authors.initials: J
authors.lastname: Groopman
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Sloand
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002898:Chromosomes, Human, Pair 8; D019938:Cyclin D1 / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000009:adverse effects / Q000379:methods*; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014314:Trisomy / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D013450:Sulfones; D019938:Cyclin D1; C507134:ON 01910; D005998:Glycine