Document Detail


Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na.
MedLine Citation:
PMID:  22524974     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
EXPERIMENTAL DESIGN: 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:
Matthew J Olnes; Aarthie Shenoy; Barbara Weinstein; Loretta Pfannes; Kelsey Loeliger; Zachary Tucker; Xin Tian; Minjung Kwak; Francois Wilhelm; Agnes S M Yong; Irina Maric; Manoj Maniar; Phillip Scheinberg; Jerome Groopman; Neal S Young; Elaine M Sloand
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Publication Detail:
Type:  Clinical Trial, Phase I; Journal Article; Research Support, N.I.H., Intramural     Date:  2012-04-21
Journal Detail:
Title:  Leukemia research     Volume:  36     ISSN:  1873-5835     ISO Abbreviation:  Leuk. Res.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-06-22     Completed Date:  2012-09-05     Revised Date:  2013-08-14    
Medline Journal Info:
Nlm Unique ID:  7706787     Medline TA:  Leuk Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  982-9     Citation Subset:  IM    
Copyright Information:
Published by Elsevier Ltd.
Affiliation:
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. olnesmj@nhlbi.nih.gov
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00533416
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MeSH Terms
Descriptor/Qualifier:
Aged
Aged, 80 and over
Algorithms
Antineoplastic Agents / administration & dosage,  adverse effects,  pharmacology,  therapeutic use
Bone Marrow Cells / drug effects,  pathology
Chromosomes, Human, Pair 8
Cyclin D1 / antagonists & inhibitors*
Dose-Response Relationship, Drug
Female
Glycine / administration & dosage,  adverse effects,  analogs & derivatives*,  pharmacology,  therapeutic use
Humans
Male
Middle Aged
Molecular Targeted Therapy / adverse effects,  methods*
Myelodysplastic Syndromes / drug therapy*,  genetics,  pathology
Sulfones / administration & dosage,  adverse effects,  pharmacology,  therapeutic use*
Trisomy / pathology
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
Z99 HL999999/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/ON 01910; 0/Sulfones; 136601-57-5/Cyclin D1; 56-40-6/Glycine
Comments/Corrections
Comment In:
Leuk Res. 2012 Aug;36(8):964-5   [PMID:  22607960 ]

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