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

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• 作者：Matthew J. Olnes^a ; ^b ; ^{olnesmj@nhlbi.nih.gov} ; ^{mjolnes@anthc.org} ; Aarthie Shenoy^a ; Barbara Weinstein^a ; Loretta Pfannes^a ; Kelsey Loeliger^a ; Zachary Tucker^a ; Xin Tian^e ; Minjung Kwak^e ; Francois Wilhelm^c ; Agnes S.M. Yong^a ; Irina Maric^f ; Manoj Maniar^c ; Phillip Scheinberg^a ; Jerome Groopman^d ; Neal S. Young^a ; Elaine M. Sloand^a ; ¹
• 关键词：MDS ; Treatment ; ON 01910.Na ; Cyclin D1
• 刊名：Leukemia Research
• 出版年：2012
• 期刊代码：186_01452126
• 类别：med
• 出版时间：August, 2012
• 卷：36
• 期：8
• 页码：982-989
• 文件大小：658 K

摘要

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). 鈥淜nockdown鈥?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 ().

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 鈮?0%, 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.