Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair

Abstract

BackgroundDespite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylating activity.MethodsThe efficacy of EDO-S101 was evaluated in vitro, ex vivo and in vivo, alone, and in combination with standard anti-myeloma agents. The underlying mechanisms of action were also evaluated on MM cell lines, patient samples, and different murine models.ResultsEDO-S101 displayed potent activity in vitro in MM cell lines (IC50 1.6–4.8 μM) and ex vivo in cells isolated from MM patients, which was higher than that of bendamustine and independent of the p53 status and previous melphalan resistance. This activity was confirmed in vivo, in a CB17-SCID murine plasmacytoma model and in de novo Vk*MYC mice, leading to a significant survival improvement in both models. In addition, EDO-S101 was the only drug with single-agent activity in the multidrug resistant Vk12653 murine model. Attending to its mechanism of action, the molecule showed both, a HDACi effect (demonstrated by α-tubulin and histone hyperacetylation) and a DNA-damaging effect (shown by an increase in γH2AX); the latter being again clearly more potent than that of bendamustine. Using a reporter plasmid integrated into the genome of some MM cell lines, we demonstrate that, apart from inducing a potent DNA damage, EDO-S101 specifically inhibited the double strand break repair by the homologous recombination pathway. Moreover, EDO-S101 treatment reduced the recruitment of repair proteins such as RAD51 to DNA-damage sites identified as γH2AX foci. Finally, EDO-S101 preclinically synergized with bortezomib, both in vitro and in vivo.ConclusionThese findings provide rationale for the clinical investigation of EDO-S101 in MM, either as a single agent or in combination with other anti-MM drugs, particularly proteasome inhibitors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0495-y) contains supplementary material, which is available to authorized users.

The Multiple Myeloma Drug Pipeline—2018: A Review of Small Molecules and Their Therapeutic Targets

“…Tinostamustine (EDO-S101), a fusion molecule that combines the molecular features of bendamustine and the HDAC inhibitor vorinostat, was reported to display good activity in preclinical studies of myeloma patient cells. 7 This agent now is in a phase I trial (ClinicalTrials.gov identifier, NCT02576496) of patients with lymphoma and myeloma previously shown to be refractory to treatment (Table 1).…”

“…66 Tinostamustine (EDO-S101), mentioned earlier as a fusion product linking vorinostat with the DNA-damaging alkylating agent bendamustine, selectively inhibits HDACs 1, 2, and 6, blocks HDAC-associated DNA repair, and has demonstrated antitumor activity in both cell culture and xenograph models. 7…”

Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia

“…erefore, a novel DNA/HDAC dual targeting compound NL-101 that combines the nitrogen mustard group of bendamustine with the hydroxamic acid group of vorinostat was designed. It exerts a potent antitumor ability in multiple myeloma [18] and acute myeloid leukemia [19]. However, its activity in T-ALL was not investigated.…”

Cladribine in combination with entinostat synergistically elicits anti-proliferative/anti-survival effects on multiple myeloma cells

“…First, while we found an upregulation of p27 kip−1 expression in MM1.R cells upon treatment with cladribine and/or entinostat, the expression of p27 kip−1 in RPMI8226 cells was dramatically decreased by the combinatorial treatment (Figure 4). By screening gene type in the MM cells, we discovered that MM1.R and RPMI8226 cells contained distinct gene phenotype of p53 , which could serve as the upstream signaling protein of p27 kip−1 [55,56]. Thus, we speculated that the mutant p53 gene expression might cause the different response of p27 kip−1 in the two MM cell lines.…”