1951 年摘要：SMAC 模拟物和 BET 抑制剂 - 用于实体癌治疗的有希望的组合,Cancer Research

当前位置： X-MOL 学术 › Cancer Res. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

1951 年摘要：SMAC 模拟物和 BET 抑制剂 - 用于实体癌治疗的有希望的组合
Cancer Research ( IF 12.5 ) Pub Date : 2021-07-01 , DOI: 10.1158/1538-7445.am2021-1951
Paula-Elena Traexler ₁ , Dominik Arnold ₂ , Florian Ebner ₂ , Ksenija Slavic-Obradovic ₂ , Robin Jacob ₂ , Ha Pham Thi Thanh ₂ , Martin Aichinger ₂ , Anke Baum ₂ , Andreas Wernitznig ₂ , Daniel Gerlach ₂ , Maria-Antonietta Impagnatiello ₂ , Valeria Santoro ₂ , Sabine Olt ₂ , Dirk Scharn ₂ , Regina Ruzicka ₂ , Reniqua P. House ₃ , Mary Y. Murphy ₃ , Ulrich Reiser ₂ , Harald Engelhardt ₂ , Vittoria Zinzalla ₂ , Thorsten Laux ₄ , Flavio Solca ₂ , Ulrike Tontsch-Grunt ₂

Affiliation

摘要 SMAC 模拟物 (SMACm) 是一种模拟细胞凋亡抑制剂 (IAP) 天然拮抗剂的药物，目前正处于血液系统恶性肿瘤和实体癌的临床试验中。迄今为止，单一疗法对患者的临床益处令人沮丧。因此，目前对 SMACm 的临床评估侧重于组合，特别是与检查点抑制剂和/或放射治疗的组合。BET 家族蛋白 BRD4 是表观遗传信息的“阅读器”，并与乙酰化染色质结合，作为转录的关键调节因子。BET 抑制剂 (BETi) 在许多临床试验中作为血液和实体癌的新治疗选择进行了测试。与 SMACm 一样，BETi 单药治疗仅表现出适度的临床活性，强调了联合试验的重要性。BI 891065 一种单价口服 SMACm，具有良好的安全性，允许连续给药，处于临床 I 期（NCT03166631，NCT04138823）。BI 894999 是一种非常有效和选择性的口服 BETi，在临床 I 期 (NCT02516553) 中通过间歇给药方式给药。我们使用 Bliss 协同分析和 IncuCyte ZOOM® 活细胞成像在体外研究了这两种化合物在大量人类肿瘤细胞系（肺癌、结肠直肠癌、胰腺癌和胃癌）中的增殖试验中的组合效应，以及在体内的三个独立模型。在 60 多种癌细胞系中，约 30% 在使用 BI 891065 + BI 894999 组合治疗时显示出协同作用，无论适应症如何。功效与 BI 894999 下调关键的凋亡调节因子 XIAP 相关。在大多数测试的细胞系中，通过添加 TNFα 清除剂 Enbrel 和/或凋亡途径抑制剂 zVAD 阻断协同作用。在两种 PDAC 异种移植模型（一种免疫活性和一种免疫缺陷）和一种 CRC 模型中以临床相关剂量测试了体内功效。两种化合物的每日口服应用都具有良好的耐受性并且不会导致药物-药物相互作用。目标参与标记按预期进行调制（SMACm 的 cIAP1 降解和 BETi 的 Hexim1 诱导）并且不受组合的影响。在 BxPC3 胰腺模型中，50 mg/kg BI 891065 的肿瘤生长抑制达到 22% TGI，2 mg/kg BI 894999 的 TGI 达到 70%，组合达到 96% TGI。在 Pan02 胰腺模型中，记录了 50 mg/kg BI 891065 的 9% TGI、4 mg/kg BI 894999 的 30% TGI 和组合的 92% TGI。在这种免疫活性模型中评估肿瘤微环境的细胞组成显示出明显的变化，即联合治疗后免疫抑制环境减少。在 CRC 模型 LoVo 中，对肿瘤生长的组合效应远没有那么明显。这些临床前体外和体内数据突出了 SMACm/BETi 组合治疗实体癌的潜力。确定这种组合的患者选择标记对于将这一概念推进到关键的临床试验中是必要的。引文格式：Paula-Elena Traexler, Dominik Arnold, Florian Ebner, Ksenija Slavic-Obradovic, Robin Jacob, Ha Pham Thi Thanh, Martin Aichinger, Anke Baum, Andreas Wernitznig, Daniel Gerlach, Maria-Antonietta Impagnatiello, Valeria Santoro, Sabine Olt,德克·沙恩，Regina Ruzicka、Reniqua P. House、Mary Y. Murphy、Ulrich Reiser、Harald Engelhardt、Vittoria Zinzalla、Thorsten Laux、Flavio Solca、Ulrike Tontsch-Grunt。SMAC 模拟物和 BET 抑制剂 - 用于实体癌治疗的有希望的组合 [摘要]。在：美国癌症研究协会 2021 年年会论文集；2021 年 4 月 10 日至 15 日和 5 月 17 日至 21 日。费城 (PA)：AACR；癌症研究 2021；81（13_Suppl）：摘要 nr 1951。

"点击查看英文标题和摘要"

Abstract 1951: SMAC mimetic and BET inhibitor - a promising combination for solid cancer treatment

Abstract SMAC mimetics (SMACm), drugs that mimic natural antagonists of Inhibitor of Apoptosis (IAP) are in clinical trials for hematological malignancies and solid cancers. The clinical benefit for patients in monotherapy was so far dismal. Hence, current clinical evaluation of SMACm focuses on combinations, in particular with checkpoint inhibitors and/or radiation therapy. The BET family protein BRD4 is a “reader” of epigenetic information and binds to acetylated chromatin to act as a key regulator of transcription. BET inhibitors (BETi) were tested in numerous clinical trials as novel treatment option for hematological and solid cancers. Like SMACm, monotherapy with BETi showed only moderate clinical activity stressing the importance of combination trials. BI 891065 a monovalent, oral SMACm, with a favorable safety profile allowing continuous dosing, is in Clinical Phase I (NCT03166631, NCT04138823). BI 894999 is a very potent and selective oral BETi, administered by intermittent dosing in Clinical Phase I (NCT02516553). We studied the combinatorial effect of both compounds in vitro across a large number of human tumor cell lines (lung, colorectal, pancreatic, and gastric cancer) in proliferation assays using Bliss synergy analysis and IncuCyte ZOOM® live cell imaging, and in vivo in three independent models. Of the 60+ cancer cell lines, around 30% showed synergy when treated with the BI 891065 + BI 894999 combination, irrespective of indication. Efficacy correlated with downmodulation of the key apoptosis regulator XIAP by BI 894999. In most of the cell lines tested, the synergistic effect was blocked by addition of the TNFα scavenger Enbrel and/or the apoptotic pathway inhibitor zVAD. In vivo efficacy was tested in two PDAC xenograft models (one immunocompetent and one immunodeficient) and one CRC model at clinically relevant doses. Daily oral application of both compounds was well tolerated and did not lead to drug-drug interactions. Target engagement markers were modulated as expected (cIAP1 degradation for SMACm and Hexim1 induction for BETi) and not compromised by the combination. Tumor growth inhibition in the BxPC3 pancreas model achieved 22% TGI for 50 mg/kg BI 891065, 70% TGI for 2 mg/kg BI 894999, and 96% TGI for the combination. In the Pan02 pancreas model 9% TGI for 50 mg/kg BI 891065, 30% TGI for 4 mg/kg BI 894999 and 92% TGI for the combination were recorded. Evaluation of the cellular composition of the tumor microenvironment in this immunocompetent model showed distinct changes evident of a reduced immuno-suppressive milieu upon combination treatment. Combination effects on tumor growth in the CRC model LoVo were far less pronounced. These preclinical in vitro and in vivo data are highlighting the potential of a SMACm/BETi combination for the treatment of solid cancers. The identification of patient selection markers for this combination will be necessary for advancing this concept into pivotal clinical trials. Citation Format: Paula-Elena Traexler, Dominik Arnold, Florian Ebner, Ksenija Slavic-Obradovic, Robin Jacob, Ha Pham Thi Thanh, Martin Aichinger, Anke Baum, Andreas Wernitznig, Daniel Gerlach, Maria-Antonietta Impagnatiello, Valeria Santoro, Sabine Olt, Dirk Scharn, Regina Ruzicka, Reniqua P. House, Mary Y. Murphy, Ulrich Reiser, Harald Engelhardt, Vittoria Zinzalla, Thorsten Laux, Flavio Solca, Ulrike Tontsch-Grunt. SMAC mimetic and BET inhibitor - a promising combination for solid cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1951.

更新日期：2021-07-01

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南