López-Iglesias Ana-Alicia, Herrero Ana B, Chesi Marta, San-Segundo Laura, González-Méndez Lorena, Hernández-García Susana, Misiewicz-Krzeminska Irena, Quwaider Dalia, Martín-Sánchez Montserrat, Primo Daniel, Paíno Teresa, Bergsagel P Leif, Mehrling Thomas, González-Díaz Marcos, San-Miguel Jesús F, Mateos María-Victoria, Gutiérrez Norma C, Garayoa Mercedes, Ocio Enrique M
University Hospital of Salamanca (IBSAL) & Cancer Research Center (IBMCC-CSIC-USAL), Salamanca, Spain.
Comprehensive Cancer Center, Mayo Clinic, Arizona, USA.
J Hematol Oncol. 2017 Jun 20;10(1):127. doi: 10.1186/s13045-017-0495-y.
Despite 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.
The 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.
EDO-S101 displayed potent activity in vitro in MM cell lines (IC 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.
These 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.
尽管多发性骨髓瘤（MM）的治疗最近取得了进展，但大多数患者的预后仍然很差，并且对传统药物和新药的耐药性经常出现。EDO-S101是一种新型治疗药物，它是一种组蛋白去乙酰化酶抑制剂与苯达莫司汀的融合物，旨在增强其烷基化活性。
对EDO-S101单独以及与标准抗骨髓瘤药物联合使用时的体外、离体和体内疗效进行了评估。还在MM细胞系、患者样本和不同的小鼠模型上评估了其潜在的作用机制。
EDO-S101在MM细胞系中体外显示出强效活性（IC 1.6 - 4.8 μM），在从MM患者分离的细胞中离体显示出强效活性，高于苯达莫司汀，且与p53状态和先前的美法仑耐药性无关。这种活性在CB17-SCID小鼠浆细胞瘤模型和新生Vk*MYC小鼠的体内得到证实，导致两种模型的生存期均显著延长。此外，EDO-S101是多药耐药Vk12653小鼠模型中唯一具有单药活性的药物。就其作用机制而言，该分子既显示出HDACi效应（通过α-微管蛋白和组蛋白高乙酰化证明），又显示出DNA损伤效应（通过γH2AX增加显示）；后者再次明显比苯达莫司汀更强效。使用整合到一些MM细胞系基因组中的报告质粒，我们证明，除了诱导强效DNA损伤外，EDO-S101还通过同源重组途径特异性抑制双链断裂修复。此外，EDO-S101治疗减少了诸如RAD51等修复蛋白募集到被鉴定为γH2AX病灶的DNA损伤位点。最后，EDO-S101在临床前与硼替佐米在体外和体内均具有协同作用。
这些发现为EDO-S101作为单药或与其他抗MM药物（特别是蛋白酶体抑制剂）联合用于MM的临床研究提供了理论依据。
