一种用于评估卵巢癌中 PARP-1 表达的 PET 成像剂。

A PET imaging agent for evaluating PARP-1 expression in ovarian cancer.

机构信息

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

Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

出版信息

J Clin Invest. 2018 May 1;128(5):2116-2126. doi: 10.1172/JCI97992. Epub 2018 Apr 16.

DOI:10.1172/JCI97992

PMID:29509546

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5919879/

Abstract

BACKGROUND

Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in a broad population of patients with ovarian cancer; however, resistance caused by low enzyme expression of the drug target PARP-1 remains to be clinically evaluated in this context. We hypothesize that PARP-1 expression is variable in ovarian cancer and can be quantified in primary and metastatic disease using a novel PET imaging agent.

METHODS

We used a translational approach to describe the significance of PET imaging of PARP-1 in ovarian cancer. First, we produced PARP1-KO ovarian cancer cell lines using CRISPR/Cas9 gene editing to test the loss of PARP-1 as a resistance mechanism to all clinically used PARP inhibitors. Next, we performed preclinical microPET imaging studies using ovarian cancer patient-derived xenografts in mouse models. Finally, in a phase I PET imaging clinical trial we explored PET imaging as a regional marker of PARP-1 expression in primary and metastatic disease through correlative tissue histology.

RESULTS

We found that deletion of PARP1 causes resistance to all PARP inhibitors in vitro, and microPET imaging provides proof of concept as an approach to quantify PARP-1 in vivo. Clinically, we observed a spectrum of standard uptake values (SUVs) ranging from 2-12 for PARP-1 in tumors. In addition, we found a positive correlation between PET SUVs and fluorescent immunohistochemistry for PARP-1 (r2 = 0.60).

CONCLUSION

This work confirms the translational potential of a PARP-1 PET imaging agent and supports future clinical trials to test PARP-1 expression as a method to stratify patients for PARP inhibitor therapy.

TRIAL REGISTRATION

Clinicaltrials.gov NCT02637934.

FUNDING

Research reported in this publication was supported by the Department of Defense OC160269, a Basser Center team science grant, NIH National Cancer Institute R01CA174904, a Department of Energy training grant DE-SC0012476, Abramson Cancer Center Radiation Oncology pilot grants, the Marsha Rivkin Foundation, Kaleidoscope of Hope Foundation, and Paul Calabresi K12 Career Development Award 5K12CA076931.

摘要

背景

聚（ADP-核糖）聚合酶（PARP）抑制剂在广泛的卵巢癌患者中有效；然而，药物靶点 PARP-1 的低酶表达导致的耐药性仍需在这方面进行临床评估。我们假设 PARP-1 在卵巢癌中表达是可变的，可以使用新型 PET 成像剂在原发性和转移性疾病中进行定量。

方法

我们采用转化方法描述 PARP-1 在卵巢癌中的 PET 成像意义。首先，我们使用 CRISPR/Cas9 基因编辑技术产生 PARP1-KO 卵巢癌细胞系，以测试 PARP-1 缺失是否作为所有临床使用的 PARP 抑制剂的耐药机制。接下来，我们在小鼠模型中进行了卵巢癌患者来源异种移植的临床前 microPET 成像研究。最后，在 I 期 PET 成像临床试验中，我们通过相关组织学探索了 PET 成像作为原发性和转移性疾病中 PARP-1 表达的区域标志物。

结果

我们发现 PARP1 的缺失导致体外所有 PARP 抑制剂的耐药性，microPET 成像提供了一种在体内定量 PARP-1 的概念验证方法。临床上，我们观察到肿瘤中 PARP-1 的标准摄取值（SUV）范围从 2-12。此外，我们发现 PET SUV 与 PARP-1 的荧光免疫组织化学呈正相关（r2 = 0.60）。

结论

这项工作证实了 PARP-1 PET 成像剂的转化潜力，并支持未来的临床试验，以测试 PARP-1 表达作为 PARP 抑制剂治疗分层患者的方法。

试验注册

Clinicaltrials.gov NCT02637934。

资金

本研究报告的研究由国防部 OC160269、Basser 中心团队科学资助、NIH 国家癌症研究所 R01CA174904、能源部培训资助 DE-SC0012476、Abramson 癌症中心放射肿瘤学试点资助、Marsha Rivkin 基金会、万花筒希望基金会和 Paul Calabresi K12 职业发展奖 5K12CA076931 支持。