The Survivin Suppressant YM155 (Sepantronium Bromide) Has Potent Pre-Clinical Activity Against Pediatric Acute Myeloid Leukemia
Authors: Little Erica B. , Smith Amanda M. , Zivanovic Andjelija , Liu Alfred K.S. , Waldron Shannon , Ingram Wendy J. , Hallahan Andrew R. , Moore Andrew S. 
Published: October 2019

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.Table 1In vitro sensitivity of AML cell lines to YM155, cytarabine and daunorubicin, as measured by 72 hour cell viability (resazurin reduction) assays. Values indicate median IC50(µM) from at least 3 independent experiments. *Pediatric AML cell lines. NS, not significant.AML Cell LineCharacteristic FeatureYM155CytarabineDaunorubicinP value (YM155 vs. Cytarabine)HL-60Complex karyotype0.0010.4810.019NSKasumi-1*t(8;21)(q22;q22)0.0100.1120.0220.011RUNX1-CBFA2T1c-KITmut(N822K)ML-2t(6;11)(q27;q23)0.0100.0620.0050.027OCI/AML3NPM1mut0.011>100.020<0.001MV4-11*t(4;11)(q21;q23)0.0301.2630.004<0.001MLL-AF4FLT3-ITDTHP-1*t(9;11)(p21;q23)0.0367.0440.027<0.001CMK*AML assoc. with Down Syndrome0.0530.4280.078<0.001HELAML M60.5310.0780.1310.011ME-1inv(16)(p13q22)0.6800.3900.298NSCBFB-MYH11

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.

Disclosures:

No relevant conflicts of interest to declare.