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替曲膦用于高危神经母细胞瘤的临床前研究。

Pre-clinical investigation of astatine-211-parthanatine for high-risk neuroblastoma.

机构信息

Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA, 19104, USA.

出版信息

Commun Biol. 2022 Nov 17;5(1):1260. doi: 10.1038/s42003-022-04209-8.

DOI:10.1038/s42003-022-04209-8
PMID:36396952
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9671962/
Abstract

Astatine-211-parthanatine ([At]PTT) is an alpha-emitting radiopharmaceutical therapeutic that targets poly(adenosine-diphosphate-ribose) polymerase 1 (PARP1) in cancer cells. High-risk neuroblastomas exhibit among the highest PARP1 expression across solid tumors. In this study, we evaluated the efficacy of [At]PTT using 11 patient-derived xenograft (PDX) mouse models of high-risk neuroblastoma, and assessed hematological and marrow toxicity in a CB57/BL6 healthy mouse model. We observed broad efficacy in PDX models treated with [At]PTT at the maximum tolerated dose (MTD 36 MBq/kg/fraction x4) administered as a fractionated regimen. For the MTD, complete tumor response was observed in 81.8% (18 of 22) of tumors and the median event free survival was 72 days with 30% (6/20) of mice showing no measurable tumor >95 days. Reversible hematological and marrow toxicity was observed 72 hours post-treatment at the MTD, however full recovery was evident by 4 weeks post-therapy. These data support clinical development of [At]PTT for high-risk neuroblastoma.

摘要

[211At] 帕他膦酸盐 ([At]PTT) 是一种靶向聚（二磷酸腺苷核糖）聚合酶 1（PARP1）的 α 发射放射性药物治疗剂，在癌细胞中。高危神经母细胞瘤在实体瘤中表现出最高的 PARP1 表达之一。在这项研究中，我们使用 11 种源自患者的异种移植 (PDX) 高危神经母细胞瘤小鼠模型评估了 [At]PTT 的疗效，并在 CB57/BL6 健康小鼠模型中评估了血液学和骨髓毒性。我们观察到，以 4 次分割方案给予最大耐受剂量（MTD 36 MBq/kg/分次 x4）的 [At]PTT 在 PDX 模型中表现出广泛的疗效。对于 MTD，81.8%（22 个中的 18 个）的肿瘤观察到完全肿瘤反应，无肿瘤可测量>95 天的小鼠比例为 30%（20 个中的 6 个），中位无事件生存时间为 72 天。在 MTD 后 72 小时观察到可逆的血液学和骨髓毒性，但在治疗后 4 周完全恢复。这些数据支持 [At]PTT 用于高危神经母细胞瘤的临床开发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eb3/9671962/091c0399e127/42003_2022_4209_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eb3/9671962/5a6d801232b8/42003_2022_4209_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eb3/9671962/1f2054d6b8ec/42003_2022_4209_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eb3/9671962/091c0399e127/42003_2022_4209_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eb3/9671962/5a6d801232b8/42003_2022_4209_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eb3/9671962/1f2054d6b8ec/42003_2022_4209_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eb3/9671962/091c0399e127/42003_2022_4209_Fig3_HTML.jpg

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本文引用的文献

[1]
Comparison of absorbed dose extrapolation methods for mouse-to-human translation of radiolabelled macromolecules.

EJNMMI Res. 2022-4-11

[2]
Combination of Carriers with Complementary Intratumoral Microdistributions of Delivered -Particles May Realize the Promise for Ac in Large, Solid Tumors.

J Nucl Med. 2022-8

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In vivo visualization of PARP inhibitor pharmacodynamics.

JCI Insight. 2021-4-22

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Extended single-dose toxicity study of [At]NaAt in mice for the first-in-human clinical trial of targeted alpha therapy for differentiated thyroid cancer.

Ann Nucl Med. 2021-6

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J Nucl Med. 2022-1

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The B7-H3-Targeting Antibody-Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models.

Clin Cancer Res. 2021-5-15

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PARP Targeted Alpha-Particle Therapy Enhances Response to PD-1 Immune-Checkpoint Blockade in a Syngeneic Mouse Model of Glioblastoma.

ACS Pharmacol Transl Sci. 2021-1-26

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PARP Theranostic Auger Emitters Are Cytotoxic in BRCA Mutant Ovarian Cancer and Viable Tumors from Ovarian Cancer Patients Enable Ex-Vivo Screening of Tumor Response.

Molecules. 2020-12-19

[9]
Radiopharmaceutical therapy in cancer: clinical advances and challenges.

Nat Rev Drug Discov. 2020-7-29

[10]
Assessment of PARP-1 Distribution in Tissues of Cynomolgus Monkeys.

J Histochem Cytochem. 2020-5-21

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