摘要:STC-15是一种新型METTL3抑制剂,它与Venetoclax联合在AML模型中具有抗肿瘤活性

IF 11.5 Q1 HEMATOLOGY
L. Vasiliauskaitė, Y. Ofir-Rosenfeld, M. Albertella, C. Hoareau-Aveilla, Jerry McMahon, Oliver Rausch
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Storm Therapeutics has developed potent and selective METTL3 inhibitors, including the clinical candidate STC-15. Here, we explore pharmacological inhibition of METTL3 as monotherapy or in combination with Venetoclax in AML models in vitro and in vivo. Sulforhodamine B and CellTiterGloTM assays were used to assess the viability of AML cell lines and patient-derived xenografts (PDXs), respectively, following METTL3 inhibition in vitro. BCL2 protein level was evaluated by Western blotting. SynergyFinder software was used to assess the degree of synergy between METTL3 inhibitors and Venetoclax. Intra-tibial implantation of human-derived AML cells (AML-PDXs) in NSG mice was used to determine single agent and combination therapy efficacy. Multiple AML cells lines and AML-PDXs were sensitive to pharmacological inhibition of METTL3 in vitro, as assessed by loss of viability. Treatment with METTL3 inhibitors led to downregulation of BCL2 protein level in several AML cell lines, as previously suggested by literature. Based on these results, the synergy between METTL3 inhibition and Venetoclax was assessed. Matrix-combination experiments have shown a high degree of synergy between the two drugs (defined by a synergy score >10) in THP-1 and MOLM-13 cell lines. To test METTL3 inhibition as a monotherapy and in combination with Venetoclax in vivo, three AML-PDX studies were initiated. Significantly lower spleen weight was observed in all animals treated with STC-15 or STC-15 + Venetoclax, and reduced number of circulating hCD45+ cells was observed in 2 out of the 3 models. In one of the models, STC-15 monotherapy outperformed Venetoclax (median survival 68 days vs 58 days, respectively), while the combination therapy extended median group survival to 85 days in comparison to 51.5 days in the vehicle group. In conclusion, we demonstrated that METTL3 inhibition results in anti-tumour effects across different AML models. Moreover, we demonstrated a synergistic effect between the novel METTL3 inhibitor STC-15 and Venetoclax, both in vitro and in vivo. These studies provide evidence for the utility of METTL3 inhibitor as a new therapeutic agent to treat AML. Currently, STC-15 is under clinical development (NCT05584111).\n Citation Format: Lina Vasiliauskaite, Yaara Ofir-Rosenfeld, Mark Albertella, Coralie Hoareau-Aveilla, Jerry McMahon, Oliver Rausch. STC-15, a novel METTL3 inhibitor, and its combination with Venetoclax confer anti-tumour activity in AML models [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. 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引用次数: 0

摘要

n6 -甲基腺苷(m6A)是最丰富的RNA修饰之一,影响mRNA和lncRNA的定位、半衰期、翻译和剪接。细胞mrna上的大多数m6A修饰是由RNA甲基转移酶METTL3沉积的。迄今为止,METTL3已与多种癌症类型的发生和进展有关,在急性髓性白血病(AML)中观察到METTL3 mRNA的最高表达。目前,AML患者的一种标准治疗方法是Venetoclax,其靶向抗凋亡蛋白BCL2。结果表明,m6A通过METTL3沉积在BCL2转录本上,影响BCL2 mRNA的稳定性和翻译。Storm Therapeutics已经开发出强效和选择性的METTL3抑制剂,包括临床候选药物STC-15。在这里,我们探讨了METTL3作为单一疗法或与Venetoclax联合治疗在体外和体内AML模型中的药理抑制作用。使用Sulforhodamine B和CellTiterGloTM检测分别评估体外METTL3抑制后AML细胞系和患者来源的异种移植物(PDXs)的活力。Western blotting检测BCL2蛋白水平。使用SynergyFinder软件评估METTL3抑制剂与Venetoclax之间的协同作用程度。采用NSG小鼠胫骨内植入人源性AML细胞(AML- pdxs),观察单药和联合治疗的疗效。多种AML细胞系和AML- pdxs对体外药理抑制METTL3敏感,通过丧失活力来评估。METTL3抑制剂治疗导致几种AML细胞系BCL2蛋白水平下调,如先前文献所述。基于这些结果,评估了METTL3抑制与Venetoclax之间的协同作用。基质联合实验表明,两种药物在THP-1和MOLM-13细胞系中具有高度的协同作用(协同作用评分为bbb10)。为了在体内测试METTL3作为单一疗法和与Venetoclax联合使用的抑制作用,启动了三项AML-PDX研究。STC-15或STC-15 + Venetoclax处理的所有动物脾脏重量均显著降低,3个模型中有2个模型的循环hCD45+细胞数量减少。在其中一个模型中,STC-15单药治疗优于Venetoclax(中位生存期分别为68天和58天),而联合治疗将中位组生存期延长至85天,而载体组为51.5天。总之,我们证明了METTL3抑制在不同的AML模型中产生抗肿瘤作用。此外,我们证明了新型METTL3抑制剂STC-15和Venetoclax在体外和体内都具有协同效应。这些研究为METTL3抑制剂作为治疗AML的新药物提供了证据。目前,STC-15正在临床开发中(NCT05584111)。引文格式:Lina Vasiliauskaite, Yaara ofirl - rosenfeld, Mark Albertella, Coralie Hoareau-Aveilla, Jerry McMahon, Oliver Rausch。STC-15是一种新型的METTL3抑制剂,它与Venetoclax联合在AML模型中具有抗肿瘤活性[摘要]。摘自:AACR特别会议论文集:急性髓性白血病和骨髓增生异常综合征;2023年1月23-25日;费城(PA): AACR;血癌发现[j]; 2009;4(3 -增刊):摘要nr A18。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Abstract A18: STC-15, a novel METTL3 inhibitor, and its combination with Venetoclax confer anti-tumour activity in AML models
N6-methyladenosine (m6A) is one of the most abundant RNA modifications, which influences mRNA and lncRNA localization, half-life, translation, and splicing. The majority of m6A modifications on cellular mRNAs are deposited by the RNA methyltransferase METTL3. To date, METTL3 has been implicated in the initiation and progression of multiple cancer types, with the highest expression of METTL3 mRNA observed in acute myeloid leukemia (AML). Currently, one line of standard of care therapy for AML patients is Venetoclax, which targets the anti-apoptotic protein BCL2. It was shown that m6A, deposited by METTL3 on BCL2 transcript, affects BCL2 mRNA stability and translation. Storm Therapeutics has developed potent and selective METTL3 inhibitors, including the clinical candidate STC-15. Here, we explore pharmacological inhibition of METTL3 as monotherapy or in combination with Venetoclax in AML models in vitro and in vivo. Sulforhodamine B and CellTiterGloTM assays were used to assess the viability of AML cell lines and patient-derived xenografts (PDXs), respectively, following METTL3 inhibition in vitro. BCL2 protein level was evaluated by Western blotting. SynergyFinder software was used to assess the degree of synergy between METTL3 inhibitors and Venetoclax. Intra-tibial implantation of human-derived AML cells (AML-PDXs) in NSG mice was used to determine single agent and combination therapy efficacy. Multiple AML cells lines and AML-PDXs were sensitive to pharmacological inhibition of METTL3 in vitro, as assessed by loss of viability. Treatment with METTL3 inhibitors led to downregulation of BCL2 protein level in several AML cell lines, as previously suggested by literature. Based on these results, the synergy between METTL3 inhibition and Venetoclax was assessed. Matrix-combination experiments have shown a high degree of synergy between the two drugs (defined by a synergy score >10) in THP-1 and MOLM-13 cell lines. To test METTL3 inhibition as a monotherapy and in combination with Venetoclax in vivo, three AML-PDX studies were initiated. Significantly lower spleen weight was observed in all animals treated with STC-15 or STC-15 + Venetoclax, and reduced number of circulating hCD45+ cells was observed in 2 out of the 3 models. In one of the models, STC-15 monotherapy outperformed Venetoclax (median survival 68 days vs 58 days, respectively), while the combination therapy extended median group survival to 85 days in comparison to 51.5 days in the vehicle group. In conclusion, we demonstrated that METTL3 inhibition results in anti-tumour effects across different AML models. Moreover, we demonstrated a synergistic effect between the novel METTL3 inhibitor STC-15 and Venetoclax, both in vitro and in vivo. These studies provide evidence for the utility of METTL3 inhibitor as a new therapeutic agent to treat AML. Currently, STC-15 is under clinical development (NCT05584111). Citation Format: Lina Vasiliauskaite, Yaara Ofir-Rosenfeld, Mark Albertella, Coralie Hoareau-Aveilla, Jerry McMahon, Oliver Rausch. STC-15, a novel METTL3 inhibitor, and its combination with Venetoclax confer anti-tumour activity in AML models [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A18.
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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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