Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer.
Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer.
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DOI：
10.3390/cancers12123784
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发表时间：
2020-12-15
期刊：
影响因子：
5.2
通讯作者：
Annunziata CM
中科院分区：
文献类型：
--
作者：
Noonan AM;Cousins A;Anderson D;Zeligs KP;Bunch K;Hernandez L;Shibuya Y;Goldlust IS;Guha R;Ferrer M;Thomas CJ;Annunziata CM
复发性卵巢癌由于化疗耐药性的发展而难以治疗。这种抗性通过多种机制发展，包括避免癌细胞的细胞死亡。先前的研究表明，birinapant，第二种线粒体半胱天冬酶激活剂（SMAC）模拟药物，有望克服这种获得性耐药性。然而，尽管耐受性良好，单药birinapant治疗在复发性卵巢癌女性中表现出最小的抗癌活性。通过使用高通量药物筛选，我们能够确定增强birinapant活性的潜在治疗药物，多西他赛由于其显著的协同作用和已知的在复发性卵巢癌环境中的效用而有利地出现。我们表明，这种协同作用是几种互补分子途径的结果，并希望突出这种治疗药物组合在临床试验中的潜力，其中治疗选择往往有限。 凋亡抑制因子（IAP）蛋白在卵巢癌中频繁上调，导致凋亡逃避和细胞存活增加。Birinapant是一种合成的第二线粒体半胱天冬酶激活剂（SMAC）模拟物，可抑制IAP蛋白的功能，以增强凋亡途径并促进肿瘤死亡。然而，尽管有靶向活性，单药birinapant的临床前试验在复发性卵巢癌背景下显示出最小的活性。为了增强birinapant的治疗潜力，我们利用高通量筛选矩阵来鉴定协同药物组合。在鉴定的这些组合中，选择birinapant加多西他赛进行进一步评价，因为其在体外和体内均具有显著的协同作用。我们发现，这种协同作用是由多个会聚途径引起的，包括caspase活化增加、紫杉醇介导的TNF-α上调、替代性NF-κ B信号传导和birinapant诱导的微管稳定。这些发现为在复发性卵巢癌的2期临床试验中整合birinapant和多西他赛提供了依据，其中治疗选择通常有限且效果最低。
Recurrent ovarian cancer is difficult to treat due to the development of chemotherapy resistance. This resistance develops through multiple mechanisms to include the avoidance of cell death by cancer cells. Prior studies have shown birinapant, a second mitochondrial activator of caspases (SMAC) mimetic drug, to be promising in overcoming this acquired resistance. Despite good tolerability, however, therapy with single-agent birinapant exhibited minimal anti-cancer activity in women with recurrent ovarian cancer. By using a high-throughput drug screen we were able to identify potential therapeutic agents that augment birinapant activity, with docetaxel emerging favorably due to its marked synergy and known utility in the recurrent ovarian cancer setting. We showed that this synergy is the result of several complementary molecular pathways and hope to highlight the promising potential of this therapeutic drug combination for clinical testing where treatment options are often limited. Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations. Of those combinations identified, birinapant plus docetaxel was selected for further evaluation, given its remarkable synergy both in vitro and in vivo. We showed that this synergy results from multiple convergent pathways to include increased caspase activation, docetaxel-mediated TNF-α upregulation, alternative NF-kB signaling, and birinapant-induced microtubule stabilization. These findings provide a rationale for the integration of birinapant and docetaxel in a phase 2 clinical trial for recurrent ovarian cancer where treatment options are often limited and minimally effective.
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影响因子：
6.2
作者：
Noonan AM;Bunch KP;Chen JQ;Herrmann MA;Lee JM;Kohn EC;O'Sullivan CC;Jordan E;Houston N;Takebe N;Kinders RJ;Cao L;Peer CJ;Figg WD;Annunziata CM
通讯作者：
Annunziata CM
影响因子：
--
作者：
Guha R;Mathews Griner LA;Keller JM;Zhang X;Fitzgerald D;Antignani A;Pastan I;Thomas CJ;Ferrer M
通讯作者：
Ferrer M
影响因子：
3.8
作者：
Perimenis, Philippos;Galaris, Apostolos;Pintzas, Alexander
通讯作者：
Pintzas, Alexander
影响因子：
5.7
作者：
Benetatos, Christopher A.;Mitsuuchi, Yasuhiro;Chunduru, Srinivas K.
通讯作者：
Chunduru, Srinivas K.
影响因子：
12.4
作者：
Lalaoui, Najoua;Merino, Delphine;Silke, John
通讯作者：
Silke, John