Effective Delivery of a Microtubule Polymerization Inhibitor Synergizes with Standard Regimens in Models of Pancreatic Ductal Adenocarcinoma
Effective Delivery of a Microtubule Polymerization Inhibitor Synergizes with Standard Regimens in Models of Pancreatic Ductal Adenocarcinoma
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DOI：
10.1158/1078-0432.ccr-18-3281
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发表时间：
2019-09-01
影响因子：
11.5
通讯作者：
Olive, Kenneth P.
中科院分区：
文献类型：
--
作者：
Eberle-Singh, Jaime A.;Sagalovskiy, Irina;Olive, Kenneth P.
目的：胰腺导管腺癌（PDA）是一种广泛耐药的致死性癌症，部分原因是肿瘤基质的生物物理特性，其作为大多数经典化疗药物的药物递送屏障。PTC 596是一种在体外具有强效抗癌特性并在体内具有理想药理学特性的新型药物，本研究的目的是评估PTC 596的临床前疗效和机制。实验设计：我们使用多种PDA临床前模型，评估PTC 596与标准治疗相结合的药理学、机制和临床前疗效。我们发现PTC 596具有克服PDA中药物递送障碍的药理学特性，包括长循环半衰期，缺乏P-糖蛋白底物活性和高全身耐受性。我们还发现，PTC 596与标准临床方案协同组合，以提高多个模型系统的功效，包括PDA的化学抗性基因工程“KPC”模型。通过机制研究，我们了解到PTC 596作为直接微管聚合抑制剂发挥作用，但先前的临床试验发现，与其他此类药物相比，它缺乏外周神经毒性。引人注目的是，我们发现PTC 596与标准临床骨干方案吉西他滨/nab-紫杉醇协同作用，在PDX模型中产生有效、持久的消退。此外，实现了类似的疗效与白蛋白结合型紫杉醇单独，突出了两个不同的微管靶向药物之间的特定协同作用，在设置胰腺导管adenocarcinoma.Conclusions：这些数据表明明确的理由PTC 596的发展与标准的护理化疗PDA相结合。
Purpose: Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer that is broadly chemoresistant, due in part to biophysical properties of tumor stroma, which serves as a barrier to drug delivery for most classical chemotherapeutic drugs. The goal of this work is to evaluate the preclinical efficacy and mechanisms of PTC596, a novel agent with potent anticancer properties in vitro and desirable pharmacologic properties in vivo.Experimental Design: We assessed the pharmacology, mechanism, and preclinical efficacy of PTC596 in combination with standards of care, using multiple preclinical models of PDA.Results: We found that PTC596 has pharmacologic properties that overcome the barrier to drug delivery in PDA, including a long circulating half-life, lack of P-glycoprotein substrate activity, and high systemic tolerability. We also found that PTC596 combined synergistically with standard clinical regimens to improve efficacy in multiple model systems, including the chemoresistant genetically engineered "KPC" model of PDA. Through mechanistic studies, we learned that PTC596 functions as a direct microtubule polymerization inhibitor, yet a prior clinical trial found that it lacks peripheral neurotoxicity, in contrast to other such agents. Strikingly, we found that PTC596 synergized with the standard clinical backbone regimen gemcitabine/nab-paclitaxel, yielding potent, durable regressions in a PDX model. Moreover, similar efficacy was achieved in combination with nab-paclitaxel alone, highlighting a specific synergistic interaction between two different microtubule-targeted agents in the setting of pancreatic ductal adenocarcinoma.Conclusions: These data demonstrate clear rationale for the development of PTC596 in combination with standard-of-care chemotherapy for PDA.