靶向 CD24 的荧光成像在高级别浆液性卵巢癌患者来源异种移植模型中的应用。
CD24-targeted fluorescence imaging in patient-derived xenograft models of high-grade serous ovarian carcinoma.
机构信息
Centre for Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Jonas Lies vei 91B, 5021 Bergen, Norway.
Centre for Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Jonas Lies vei 91B, 5021 Bergen, Norway; Department of Obstetrics and Gynecology, Haukeland University Hospital, 5021, Bergen, Norway.
出版信息
EBioMedicine. 2020 Jun;56:102782. doi: 10.1016/j.ebiom.2020.102782. Epub 2020 May 23.
BACKGROUND
The survival rate of patients with advanced high-grade serous ovarian carcinoma (HGSOC) remains disappointing. Clinically translatable orthotopic cell line xenograft models and patient-derived xenografts (PDXs) may aid the implementation of more personalised treatment approaches. Although orthotopic PDX reflecting heterogeneous molecular subtypes are considered the most relevant preclinical models, their use in therapeutic development is limited by lack of appropriate imaging modalities.
METHODS
We developed novel orthotopic xenograft and PDX models for HGSOC, and applied a near-infrared fluorescently labelled monoclonal antibody targeting the cell surface antigen CD24 for non-invasive molecular imaging of epithelial ovarian cancer. CD24-Alexa Fluor 680 fluorescence imaging was compared to bioluminescence imaging in three orthotopic cell line xenograft models of ovarian cancer (OV-90, Skov-3 and Caov-3, n = 3 per model). The application of fluorescence imaging to assess treatment efficacy was performed in carboplatin-paclitaxel treated orthotopic OV-90 xenografts (n = 10), before the probe was evaluated to detect disease progression in heterogenous PDX models (n = 7).
FINDINGS
Application of the near-infrared probe, CD24-AF680, enabled both spatio-temporal visualisation of tumour development, and longitudinal therapy monitoring of orthotopic xenografts. Notably, CD24-AF680 facilitated imaging of multiple PDX models representing different histological subtypes of the disease.
INTERPRETATION
The combined implementation of CD24-AF680 and orthotopic PDX models creates a state-of-the-art preclinical platform which will impact the identification and validation of new targeted therapies, fluorescence image-guided surgery, and ultimately the outcome for HGSOC patients.
FUNDING
This study was supported by the H2020 program MSCA-ITN [675743], Helse Vest RHF, and Helse Bergen HF [911809, 911852, 912171, 240222, HV1269], as well as by The Norwegian Cancer Society [182735], and The Research Council of Norway through its Centers of excellence funding scheme [223250, 262652].
背景
晚期高级别浆液性卵巢癌（HGSOC）患者的生存率仍然令人失望。临床可转化的原位细胞系异种移植模型和患者来源的异种移植（PDX）可帮助实施更个性化的治疗方法。尽管反映异质分子亚型的原位 PDX 被认为是最相关的临床前模型，但由于缺乏适当的成像方式，其在治疗开发中的应用受到限制。
方法
我们为 HGSOC 开发了新型的原位异种移植和 PDX 模型，并应用了一种针对细胞表面抗原 CD24 的近红外荧光标记的单克隆抗体，用于上皮性卵巢癌的分子无创成像。在三种卵巢癌原位细胞系异种移植模型（OV-90、Skov-3 和 Caov-3，每个模型 n=3）中比较了 CD24-Alexa Fluor 680 荧光成像和生物发光成像。在顺铂-紫杉醇治疗的 OV-90 原位异种移植中进行了荧光成像以评估治疗效果（n=10），然后在异质 PDX 模型中评估了该探针以检测疾病进展（n=7）。
结果
近红外探针 CD24-AF680 的应用实现了肿瘤发展的时空可视化，并对原位异种移植进行了纵向治疗监测。值得注意的是，CD24-AF680 促进了代表疾病不同组织学亚型的多个 PDX 模型的成像。
解释
CD24-AF680 和原位 PDX 模型的联合实施创建了一个最先进的临床前平台，将影响新靶向治疗的识别和验证、荧光图像引导手术，最终影响 HGSOC 患者的结局。
资金
本研究得到了 H2020 计划 MSCA-ITN [675743]、Helse Vest RHF 和 Helse Bergen HF [911809、911852、912171、240222、HV1269]，挪威癌症协会 [182735] 以及挪威研究理事会通过其卓越中心资助计划 [223250、262652] 的支持。
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