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 ON01910.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 ON01910.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.

A comprehensive review of myelodysplastic syndrome patients with autoimmune diseases

“…These findings support the notion that p38MAPK inhibitors along with other currently investigational approaches, namely the multi-kinase and SMAD2/3 signaling inhibitors, may prove beneficial for MDS-related AIMs. Rigosertib, a multi-kinase inhibitor that targets PI3 kinase, displayed clinical efficacy in MDS patients with increased blast counts, culminating in a substantial reduction of blastic population, hematologic improvement and extended overall survival periods [68,69]. The SMAD2/3 inhibitor has already shown erythropoietic activity in cancer patients and healthy volunteers and is being evaluated in MDS-associated anemia [70].…”

Real-time nanoscale proteomic analysis of the novel multi-kinase pathway inhibitor rigosertib to measure the response to treatment of cancer

“…The relative selective toxicity of rigosertib to malignant but not to nonmalignant normal hematopoietic cells was demonstrated dramatically in patients with MDS (49). The in vitro treatment with rigosertib of malignant blasts from patients with MDS decreased their numbers as measured by CD34 + and CD33 + bone marrow precursors, as well as measurement of Trisomy 8 (49).…”

“…The in vitro treatment with rigosertib of malignant blasts from patients with MDS decreased their numbers as measured by CD34 + and CD33 + bone marrow precursors, as well as measurement of Trisomy 8 (49). In contrast, normal human bone marrow progenitors exhibited markedly reduced toxicity to rigosertib (,50).…”

Phase I study of ON 01910.Na (Rigosertib), a multikinase PI3K inhibitor in relapsed/refractory B-cell malignancies

“…6 First-in-man studies of rigosertib in solid tumors demonstrated excellent tolerability with limited hematologic toxicity. 7 Rigosertib has also demonstrated pre-clinical and early clinical activity in myelodysplastic syndromes (MDS) 8,9 and it is currently being tested in a randomized phase III trial in patients with relapsed/refractory MDS [NCT01241500].…”