A Very Long-Acting PARP Inhibitor Suppresses Cancer Cell Growth in DNA Repair-Deficient Tumor Models.
A Very Long-Acting PARP Inhibitor Suppresses Cancer Cell Growth in DNA Repair-Deficient Tumor Models.
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DOI：
10.1158/0008-5472.can-20-1741
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发表时间：
2021-02-15
期刊：
影响因子：
11.2
通讯作者：
Santi DV
中科院分区：
文献类型：
--
作者：
Fontaine SD;Ashley GW;Houghton PJ;Kurmasheva RT;Diolaiti M;Ashworth A;Peer CJ;Nguyen R;Figg WD Sr;Beckford-Vera DR;Santi DV
PARP抑制剂被批准用于治疗具有BRCA 1或BRCA 2缺陷的癌症。在这项研究中，我们制备并表征了一种非常长效的PARP抑制剂。Talazoparib（TLZ）的大分子前药的合成通过经由β -消除性可释放接头与PEG 40 kDa载体共价缀合来实现。在小鼠异种移植物中同源重组缺陷型肿瘤的生长抑制中，单次注射PEG-TLZ缀合物与每日口服100 - 30次剂量的TLZ一样有效。这些包括具有PALB 2突变的KT-10 Wilms肿瘤，BRCA 1缺陷型MX-1三阴性乳腺癌和BRCA 2缺陷型DLD-1结肠癌;前药不抑制具有野生型BRCA 2的同基因DLD-1肿瘤。尽管PEG-化TLZ和释放的TLZ在小鼠中的半衰期仅为0.01天，但从单次安全有效剂量的前药释放的TLZ的暴露量超过了在一个月内每天给予的口服TLZ的暴露量。μPET/CT成像显示，在MX-1 BRCA 1缺陷肿瘤中，89 Zr标记的PEG-TLZ替代物具有高摄取和长时间保留。这些数据表明，前药的持久抗肿瘤作用是由于其长t1/2、前药释放的TLZ的高暴露、持续暴露后肿瘤敏感性增加和肿瘤蓄积的组合。使用TLZ在人体中的药代动力学参数，我们设计了一种长效PEG-β-TLZ，其疗效可能上级每日口服TLZ，并可用于治疗口服药物不耐受的PARP肿瘤敏感性癌症。这些发现表明，在鼠异种移植物中单次注射PARP抑制剂talazoparib的长效前药提供的肿瘤抑制相当于每日给药talazoparib一个月。
PARP inhibitors are approved for treatment of cancers with BRCA1 or BRCA2 defects. In this study, we prepared and characterized a very long-acting PARP inhibitor. Synthesis of a macromolecular prodrug of talazoparib (TLZ) was achieved by covalent conjugation to a PEG40kDa carrier via a β -eliminative releasable linker. A single injection of the PEG∼TLZ conjugate was as effective as ∼30 daily oral doses of TLZ in growth suppression of homologous recombination-defective tumors in mouse xenografts. These included the KT-10 Wilms’ tumor with a PALB2 mutation, the BRCA1-deficient MX-1 triple-negative breast cancer, and the BRCA2-deficient DLD-1 colon cancer; the prodrug did not inhibit an isogenic DLD-1 tumor with wild-type BRCA2. Although the half-life of PEG∼TLZ and released TLZ in the mouse was only ∼1 day, the exposure of released TLZ from a single safe, effective dose of the prodrug exceeded that of oral TLZ given daily over one month. μPET/CT imaging showed high uptake and prolonged retention of an 89Zr-labeled surrogate of PEG∼TLZ in the MX-1 BRCA1-deficient tumor. These data suggest that the long-lasting antitumor effect of the prodrug is due to a combination of its long t1/2, the high exposure of TLZ released from the prodrug, increased tumor sensitivity upon continued exposure, and tumor accumulation. Using pharmacokinetic parameters of TLZ in humans, we designed a long-acting PEG∼TLZ for humans that may be superior in efficacy to daily oral TLZ and would be useful for treatment of PARP inhibitor-sensitive cancers in which oral medications are not tolerated. These findings demonstrate that a single injection of a long-acting prodrug of the PARP inhibitor talazoparib in murine xenografts provides tumor suppression equivalent to a month of daily dosing of talazoparib.