Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na

• Published in: Leukemia research 2012-08, Vol.36 (8), p.982-989
• Main Authors: Olnes, Matthew J, Shenoy, Aarthie, Weinstein, Barbara, Pfannes, Loretta, Loeliger, Kelsey, Tucker, Zachary, Tian, Xin, Kwak, Minjung, Wilhelm, Francois, Yong, Agnes S.M, Maric, Irina, Maniar, Manoj, Scheinberg, Phillip, Groopman, Jerome, Young, Neal S, Sloand, Elaine M
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Algorithms; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Bone Marrow Cells - drug effects; Bone Marrow Cells - pathology; Chromosomes, Human, Pair 8; Cyclin D1; Cyclin D1 - antagonists & inhibitors; Dose-Response Relationship, Drug; Female; Glycine - administration & dosage; Glycine - adverse effects; Glycine - analogs & derivatives; Glycine - pharmacology; Glycine - therapeutic use; Hematology, Oncology and Palliative Medicine; Humans; Male; MDS; Middle Aged; Molecular Targeted Therapy - adverse effects; Molecular Targeted Therapy - methods; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; ON 01910.Na; Sulfones - administration & dosage; Sulfones - adverse effects; Sulfones - pharmacology; Sulfones - therapeutic use; Treatment; Trisomy - pathology; Tumor Cells, Cultured
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2012.04.002

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.