Lyndsey Flanagan, Aisling Coughlan, Nicola Cosgrove, Andrew Roe, Yu Wang, Stephanie Gilmore, Izabela Drozdz, Claire Comerford, Jeremy Ryan, Emma Minihane, Salma Parvin, Michael O'Dwyer, John Quinn, Philip Murphy, Simon Furney, Siobhan Glavey, Tríona Ní Chonghaile, Leukemia Research Foundation, Science Foundation Ireland, Breakthrough Cancer Research
{"title":"无类固醇的5-氮杂胞苷和venetoclax联合疗法治疗多发性骨髓瘤。","authors":"Lyndsey Flanagan, Aisling Coughlan, Nicola Cosgrove, Andrew Roe, Yu Wang, Stephanie Gilmore, Izabela Drozdz, Claire Comerford, Jeremy Ryan, Emma Minihane, Salma Parvin, Michael O'Dwyer, John Quinn, Philip Murphy, Simon Furney, Siobhan Glavey, Tríona Ní Chonghaile, Leukemia Research Foundation, Science Foundation Ireland, Breakthrough Cancer Research","doi":"10.3324/haematol.2023.283771","DOIUrl":null,"url":null,"abstract":"<p><p>Multiple myeloma (MM) is an incurable plasma cell malignancy that, despite an unprecedented increase in overall survival, lacks truly risk-adapted or targeted treatments. A proportion of patients with MM depend on BCL-2 for survival, and, recently, the BCL-2 antagonist venetoclax has shown clinical efficacy and safety in t(11;14) and BCL-2 overexpressing MM. However, only a small proportion of MM patients rely on BCL-2 (approx. 20%), and there is a need to broaden the patient population outside of t(11;14) that can be treated with venetoclax. Therefore, we took an unbiased screening approach and screened epigenetic modifiers to enhance venetoclax sensitivity in 2 non-BCL-2 dependent MM cell lines. The demethylase inhibitor 5-azacytidine was one of the lead hits from the screen, and the enhanced cell killing of the combination was confirmed in additional MM cell lines. Using dynamic BH3 profiling and immunoprecipitations, we identified the potential mechanism of synergy is due to increased NOXA expression, through the integrated stress response. Knockdown of PMAIP1 or PKR partially rescues cell death of the venetoclax and 5-azacytidine combination treatment. The addition of a steroid to the combination treatment did not enhance the cell death, and, interestingly, we found enhanced death of the immune cells with steroid addition, suggesting that a steroid-sparing regimen may be more beneficial in MM. Lastly, we show for the first time in primary MM patient samples that 5-azacytidine enhances the response to venetoclax ex vivo across diverse anti-apoptotic dependencies (BCL-2 or MCL-1) and diverse cytogenetic backgrounds. Overall, our data identify 5-azacytidine and venetoclax as an effective treatment combination, which could be a tolerable steroid-sparing regimen, particularly for elderly MM patients.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":null,"pages":null},"PeriodicalIF":8.2000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11367189/pdf/","citationCount":"0","resultStr":"{\"title\":\"Steroid-free combination of 5-azacytidine and venetoclax for the treatment of multiple myeloma.\",\"authors\":\"Lyndsey Flanagan, Aisling Coughlan, Nicola Cosgrove, Andrew Roe, Yu Wang, Stephanie Gilmore, Izabela Drozdz, Claire Comerford, Jeremy Ryan, Emma Minihane, Salma Parvin, Michael O'Dwyer, John Quinn, Philip Murphy, Simon Furney, Siobhan Glavey, Tríona Ní Chonghaile, Leukemia Research Foundation, Science Foundation Ireland, Breakthrough Cancer Research\",\"doi\":\"10.3324/haematol.2023.283771\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Multiple myeloma (MM) is an incurable plasma cell malignancy that, despite an unprecedented increase in overall survival, lacks truly risk-adapted or targeted treatments. A proportion of patients with MM depend on BCL-2 for survival, and, recently, the BCL-2 antagonist venetoclax has shown clinical efficacy and safety in t(11;14) and BCL-2 overexpressing MM. However, only a small proportion of MM patients rely on BCL-2 (approx. 20%), and there is a need to broaden the patient population outside of t(11;14) that can be treated with venetoclax. Therefore, we took an unbiased screening approach and screened epigenetic modifiers to enhance venetoclax sensitivity in 2 non-BCL-2 dependent MM cell lines. The demethylase inhibitor 5-azacytidine was one of the lead hits from the screen, and the enhanced cell killing of the combination was confirmed in additional MM cell lines. Using dynamic BH3 profiling and immunoprecipitations, we identified the potential mechanism of synergy is due to increased NOXA expression, through the integrated stress response. Knockdown of PMAIP1 or PKR partially rescues cell death of the venetoclax and 5-azacytidine combination treatment. The addition of a steroid to the combination treatment did not enhance the cell death, and, interestingly, we found enhanced death of the immune cells with steroid addition, suggesting that a steroid-sparing regimen may be more beneficial in MM. Lastly, we show for the first time in primary MM patient samples that 5-azacytidine enhances the response to venetoclax ex vivo across diverse anti-apoptotic dependencies (BCL-2 or MCL-1) and diverse cytogenetic backgrounds. Overall, our data identify 5-azacytidine and venetoclax as an effective treatment combination, which could be a tolerable steroid-sparing regimen, particularly for elderly MM patients.</p>\",\"PeriodicalId\":12964,\"journal\":{\"name\":\"Haematologica\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11367189/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Haematologica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3324/haematol.2023.283771\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Haematologica","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3324/haematol.2023.283771","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
多发性骨髓瘤(MM)是一种无法治愈的浆细胞恶性肿瘤,尽管总体生存率空前提高,但却缺乏真正适应风险的治疗或靶向治疗。一部分MM患者的生存依赖于BCL-2,最近BCL-2拮抗剂venetoclax在t(11;14)和BCL-2过表达的MM中显示出了临床疗效和安全性。然而,只有一小部分 MM 患者(约 20%)依赖 BCL-2,因此有必要扩大可接受 Venetoclax 治疗的 t(11;14)以外患者的范围。因此,我们采取了一种无偏见的筛选方法,在两种不依赖BCL-2的MM细胞系中筛选表观遗传修饰剂,以提高Venetoclax的敏感性。去甲基化酶抑制剂5-氮杂胞苷是筛选出的主要药物之一,在其他MM细胞系中也证实了联合用药可增强细胞杀伤力。通过动态 BH3 分析和免疫沉淀,我们确定了协同作用的潜在机制是通过综合应激反应增加了 NOXA 的表达。PMAIP1或PKR的敲除部分挽救了venetoclax和5-氮杂胞苷联合治疗的细胞死亡。在联合治疗中加入类固醇并不会增强细胞的死亡,有趣的是,我们发现加入类固醇后免疫细胞的死亡增强了,这表明节省类固醇的治疗方案可能对 MM 更为有益。最后,我们首次在原发性 MM 患者样本中发现,在不同的抗凋亡依赖性(BCL-2 或 MCL-1)和不同的细胞遗传背景下,5-氮杂胞苷都能增强体内外对 venetoclax 的反应。总之,我们的数据确定了5-氮杂胞苷和venetoclax是一种有效的治疗组合,这可能是一种可耐受的节省类固醇的治疗方案,尤其适用于老年MM患者。
Steroid-free combination of 5-azacytidine and venetoclax for the treatment of multiple myeloma.
Multiple myeloma (MM) is an incurable plasma cell malignancy that, despite an unprecedented increase in overall survival, lacks truly risk-adapted or targeted treatments. A proportion of patients with MM depend on BCL-2 for survival, and, recently, the BCL-2 antagonist venetoclax has shown clinical efficacy and safety in t(11;14) and BCL-2 overexpressing MM. However, only a small proportion of MM patients rely on BCL-2 (approx. 20%), and there is a need to broaden the patient population outside of t(11;14) that can be treated with venetoclax. Therefore, we took an unbiased screening approach and screened epigenetic modifiers to enhance venetoclax sensitivity in 2 non-BCL-2 dependent MM cell lines. The demethylase inhibitor 5-azacytidine was one of the lead hits from the screen, and the enhanced cell killing of the combination was confirmed in additional MM cell lines. Using dynamic BH3 profiling and immunoprecipitations, we identified the potential mechanism of synergy is due to increased NOXA expression, through the integrated stress response. Knockdown of PMAIP1 or PKR partially rescues cell death of the venetoclax and 5-azacytidine combination treatment. The addition of a steroid to the combination treatment did not enhance the cell death, and, interestingly, we found enhanced death of the immune cells with steroid addition, suggesting that a steroid-sparing regimen may be more beneficial in MM. Lastly, we show for the first time in primary MM patient samples that 5-azacytidine enhances the response to venetoclax ex vivo across diverse anti-apoptotic dependencies (BCL-2 or MCL-1) and diverse cytogenetic backgrounds. Overall, our data identify 5-azacytidine and venetoclax as an effective treatment combination, which could be a tolerable steroid-sparing regimen, particularly for elderly MM patients.
期刊介绍:
Haematologica is a journal that publishes articles within the broad field of hematology. It reports on novel findings in basic, clinical, and translational research.
Scope:
The scope of the journal includes reporting novel research results that:
Have a significant impact on understanding normal hematology or the development of hematological diseases.
Are likely to bring important changes to the diagnosis or treatment of hematological diseases.