Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models.
Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models.
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DOI：
10.18632/oncotarget.12642
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发表时间：
2017-01-17
期刊：
影响因子：
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通讯作者：
Astsaturov I
中科院分区：
文献类型：
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作者：
Bobrov E;Skobeleva N;Restifo D;Beglyarova N;Cai KQ;Handorf E;Campbell K;Proia DA;Khazak V;Golemis EA;Astsaturov I
缺乏有效的治疗方式是胰腺癌（PCa）的主要问题，胰腺癌是一种毁灭性的恶性肿瘤，几乎普遍由“不可治疗的”KRAS和TP 53癌症基因驱动。肿瘤组织渗透性差是胰腺癌耐药的主要来源，其中化疗是治疗的主要手段。在这项研究中，我们利用热休克90蛋白抑制剂的选择性肿瘤靶向特性作为药物递送到胰腺肿瘤组织的载体。STA-12-8666是HSP 90 i和拓扑异构酶I抑制剂SN-38的新型酯酶可裂解缀合物。STA-12-8666选择性结合活化的HSP 90并释放其细胞毒性有效负载，导致体内胰腺癌细胞中的药物积累。我们研究了STA-12-8666在胰腺癌的患者来源的异种移植物和遗传模型中的临床前活性。在胰腺肿瘤晚期用STA-12-8666治疗KPC小鼠（LSL-KrasG 12 D、Tp 53 fl/fl和Pdx 1-Cre转基因的敲入等位基因）使其存活率加倍（49天对74天，p=0.008）。与等摩尔剂量的伊立替康相比，STA-12-8666对5种患者来源的胰腺癌异种移植物的活性也表现出显著的上级，在一些肿瘤中具有长期缓解。STA-12-8666对肿瘤组织和匹配细胞系的活性分析表明，肿瘤中细胞毒性有效负载的长期积累和释放导致DNA损伤反应和细胞周期停滞。我们的结果提供了一个原理验证，即基于HSP 90 i的药物缀合物可以通过利用胰腺癌细胞对HSP 90拮抗剂的固有高亲和力来克服臭名昭著的治疗抗性。
The lack of effective treatment modalities is a major problem in pancreatic cancer (PCa), a devastating malignancy that is nearly universally driven by the “undruggable” KRAS and TP53 cancer genes. Poor tumor tissue penetration is the major source of resistance in pancreatic cancer where chemotherapy is the mainstay of treatment. In this study we exploited the selective tumor-targeting properties of the heat shock 90 protein inhibitors as the vehicle for drug delivery to pancreatic tumor tissues. STA-12-8666 is a novel esterase-cleavable conjugate of an HSP90i and a topoisomerase I inhibitor, SN-38. STA-12-8666 selectively binds activated HSP90 and releases its cytotoxic payload resulting in drug accumulation in pancreatic cancer cells in vivo. We investigated the preclinical activity of STA-12-8666 in patient derived xenograft and genetic models of pancreatic cancer. Treatment with STA-12-8666 of the KPC mice (knock-in alleles of LSL-KrasG12D, Tp53fl/fl and Pdx1-Cre transgene) at the advanced stages of pancreatic tumors doubled their survival (49 days vs. 74 days, p=0.008). STA-12-8666 also demonstrated dramatically superior activity in comparison to equimolar doses of irinotecan against 5 patient-derived pancreatic adenocarcinoma xenografts with prolonged remissions in some tumors. Analysis of activity of STA-12-8666 against tumor tissues and matched cell lines demonstrated prolonged accumulation and release of cytotoxic payload in the tumor leading to DNA damage response and cell cycle arrest. Our results provide a proof-of-principle validation that HSP90i-based drug conjugates can overcome the notorious treatment resistance by utilizing the inherently high affinity of pancreatic cancer cells to HSP90 antagonists.