Assayag Franck, Nicolas André, Vacher Sophie, Dehainault Catherine, Bieche Ivan, Meseure Didier, Aerts Isabelle, Cassoux Nathalie, Houdayer Claude, Doz François, Decaudin Didier
Laboratory of Preclinical Investigation, Translational Research Department, Paris Sciences et Lettres (PSL) University, Institut Curie, Paris, France.
Department of Tumor Biology, Institut Curie, Paris, France.
Invest Ophthalmol Vis Sci. 2016 Sep 1;57(11):4916-4926. doi: 10.1167/iovs.15-18725.
Retinoblastoma (Rb) is a rare childhood cancer of the retina with a survival rate of 95% in children living in high-income countries, after appropriate therapies such as chemotherapy, local ophthalmologic treatment, and radiotherapy. However, due to inactivation of the RB1 gene, all bilateral and almost 15% of unilateral retinoblastoma patients have a higher risk of s econdary cancers, especially sarcomas. Hence, new nonmutagen treatments are warranted. Therefore, we investigated the efficacy of therapy using anti-VEGF antibody bevacizumab, either alone or with carboplatin, in well-characterized Rb patient-derived xenografts (PDXs).
Three Rb PDXs previously established and characterized, RB102, RB111, and RB200, have been treated using carboplatin, bevacizumab, or carboplatin + bevacizumab. In order to define antitumor responses, various quantitative PCR and histopathologic analyses have then been performed on tumors collected at the end of experiments.
In all treated PDX models, we have observed a high and significant improvement of chemotherapy-induced in vivo efficacy by the antiangiogenic antibody. The overall response rate, lower than -0.5, was 48%, 27%, and 86% after carboplatin, bevacizumab, and carboplatin + bevacizumab, respectively (carboplatin versus carboplatin + bevacizumab; P < 10-2; bevacizumab versus carboplatin + bevacizumab; P < 10-3). In the Rb200 PDX, such a result was also observed when bevacizumab was combined with lower doses of carboplatin. Quantitative PCR and histopathologic analyses have been performed and confirmed the impact of the bevacizumab-based treatments on various angiogenic markers.
Overall, our in vivo results confirm the interest in antiangiogenic therapy for the treatment of Rb in combination with carboplatin and provide a robust rationale for testing this combination in the clinical setting for Rb patients.
视网膜母细胞瘤（Rb）是一种罕见的儿童视网膜癌症，在高收入国家，经过化疗、局部眼科治疗和放疗等适当治疗后，儿童的生存率为95%。然而，由于RB1基因失活，所有双侧以及几乎15%的单侧视网膜母细胞瘤患者发生继发性癌症的风险更高，尤其是肉瘤。因此，需要新的非诱变治疗方法。所以，我们研究了使用抗VEGF抗体贝伐单抗单独或与卡铂联合治疗在特征明确的Rb患者来源异种移植瘤（PDXs）中的疗效。
对先前建立并表征的3个Rb PDXs，即RB102、RB111和RB200，使用卡铂、贝伐单抗或卡铂+贝伐单抗进行治疗。为了确定抗肿瘤反应，随后对实验结束时收集的肿瘤进行了各种定量PCR和组织病理学分析。
在所有接受治疗的PDX模型中，我们观察到抗血管生成抗体显著提高了化疗诱导的体内疗效。总体反应率低于-0.5，卡铂、贝伐单抗和卡铂+贝伐单抗治疗后的总体反应率分别为48%、27%和86%（卡铂与卡铂+贝伐单抗相比；P<10-2；贝伐单抗与卡铂+贝伐单抗相比；P<10-3）。在Rb200 PDX中，当贝伐单抗与较低剂量的卡铂联合使用时也观察到了这样的结果。进行了定量PCR和组织病理学分析，并证实了基于贝伐单抗的治疗对各种血管生成标志物的影响。
总体而言，我们的体内研究结果证实了抗血管生成疗法与卡铂联合治疗Rb的价值，并为在Rb患者的临床环境中测试这种联合疗法提供了有力的理论依据。
