The Survivin Suppressant YM155 (Sepantronium Bromide) Has Potent Pre-Clinical Activity Against Pediatric Acute Myeloid Leukemia

Despite aggressive chemotherapy and a high remission induction rate, approximately one third of children with acute myeloid leukemia (AML) relapse. Therefore, novel and more effective treatments are urgently needed. Survivin is an inhibitor-of-apoptosis protein that plays a key role in regulating cell division, proliferation and apoptosis (Altieri et al, Nat Rev Cancer, 2008). Furthermore, high expression of survivin and its splice variants have been shown to be associated with poor clinical outcome in AML (Moore et al, ASH Abstract 3555, 2011; Carter et al, Blood, 2012). The small-molecule survivin suppressant YM155 (sepantronium bromide) has been demonstrated to have pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited, particularly in pediatric models. Therefore, we undertook a comprehensive pre-clinical evaluation of YM155 in AML, with a focus on pediatric disease.

When tested in vitro against a diverse panel of 9 AML cell lines, YM155 potently inhibited cell viability with a median IC₅₀ of 0.03 µM (range 0.001 - 0.680 µM; Table 1). All 4 pediatric cell lines tested (Kasumi-1, MV4-11, THP-1 and CMK) were particularly sensitive to YM155, with IC₅₀ values in the range of 0.010 - 0.053 µM. Of note, YM155 had generally similar in vitro efficacy to daunorubicin, but was more potent than cytarabine in 7 of the 9 cell lines.

Cell cycle analyses demonstrated concentration-dependent increases in the sub-G1 fraction of cell lines treated with YM155, suggestive of apoptosis. An apoptotic mechanism of cell death was confirmed by an increase in annexin V positivity, measured by flow cytometry. Consistent with the proposed mechanism of action, YM155 treatment also caused down-regulation of total survivin protein expression in AML cell lines.

Furthermore, in vitro assays demonstrated that YM155 was cytotoxic against a panel of 7 primary, diagnostic bone marrow samples from children with AML (median age 4.8 years, range 1.3-15.7). Patient samples were obtained from the Queensland Children's Tumour Bank and had diverse cytogenetic and molecular characteristics, including CBF-AML, monosomy 7, MLL gene rearrangements and FLT3-ITD. Similar to experiments in established cell lines, YM155 treatment caused an apoptotic response, as evidenced by induction of annexin V positivity.

In conclusion, YM155 has potent pre-clinical activity against a broad panel of AML cell lines and patient samples. Pediatric AML appears to be particularly sensitive to YM155. These data suggest that YM155-mediated inhibition of survivin is a potentially beneficial therapeutic strategy for AML, particularly childhood disease, and warrants further pre-clinical and clinical evaluation.