Abstract
Myelodysplastic syndromes (MDS) are highly heterogeneous myeloid diseases, characterized by frequent genetic/chromosomal aberrations. Olaparib is a potent, orally bioavailable poly(ADP-ribose) polymerase 1 (PARP1) inhibitor with acceptable toxicity profile, designed as targeted therapy for DNA repair defective tumors. Here, we investigated olaparib activity in primary cultures of bone marrow mononuclear cells collected from patients with MDS (n = 28). A single treatment with olaparib induced cytotoxic effects in most samples, with median IC50 of 5.4 µM (2.0–24.8 µM), lower than plasma peak concentration reached in vivo. In addition, olaparib induced DNA damage as shown by a high proportion of γH2AX positive cells in samples with low IC50s. Olaparib preferentially killed myeloid cells causing a significant reduction of blasts and promyelocytes, paralleled by an increase in metamyelocytes and mature granulocytes while sparing lymphocytes that are not part of the MDS clone. Consistently, flow cytometry analysis revealed a decrease of CD117+/CD123+ immature progenitors (p < 0.001) and induction of CD11b+/CD16+ (p < 0.001) and CD10+/CD15+ (p < 0.01) neutrophils. Morphological and immunophenotypic changes were associated with a dose-dependent increase of PU.1 and CEBPA transcription factors, which are drivers of granulocytic and monocytic differentiation. Moreover, the combination of olaparib with decitabine resulted in augmented cytotoxic and differentiating effects. Our data suggest that olaparib may have therapeutic potential in MDS patients.
Highlights
Myelodysplastic syndromes (MDS) are a group of highly heterogeneous diseases characterized by peripheral blood cytopenia, dysplasia in one or more hematopoietic cell lineages and a differentiation defect, with an increased risk of evolving to acute myeloid leukemia (AML) [1]
To assess the sensitivity of MDS to olaparib, experiments were performed using short-term cultures of MNC freshly isolated from the bone marrow (BM) samples of 28 MDS patients
We found no significant correlation between cell sensitivity, expressed as olaparib IC50 values at 7 days, and the MDS prognostic variables listed in Notably, the olaparib IC50 values were in most cases largely below the steady-state plasma peak concentrations (Cmax = 16–22 μM), measurable in patients with solid tumors receiving 300 mg olaparib twice daily [27,28]
Summary
Myelodysplastic syndromes (MDS) are a group of highly heterogeneous diseases characterized by peripheral blood cytopenia, dysplasia in one or more hematopoietic cell lineages and a differentiation defect, with an increased risk of evolving to acute myeloid leukemia (AML) [1]. Only few treatment options are available in these diseases, including growth factors in lower-risk MDS and the hypomethylating agents decitabine and azacitidine in intermediate/high-risk MDS. Both agents delay progression to AML by exerting cytotoxic and differentiating effects. Especially in patients with higher-risk MDS, Cancers 2019, 11, 1373; doi:10.3390/cancers11091373 www.mdpi.com/journal/cancers. Innovative treatment strategies are warranted for elderly and unfit patients
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