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.

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
• Journal: Leukemia research (Leuk Res) Vol. 36 Issue 8 Pg. 982-9 (Aug 2012) ISSN: 1873-5835 [Electronic] England
• PMID: 22524974 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier Ltd.

Chemical References

• Antineoplastic Agents
• Sulfones
• Cyclin D1
• ON 01910
• Glycine

Topics

• 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