Franck Assayag1, André Nicolas2, Sophie Vacher3, Catherine Dehainault3, Ivan Bieche3, Didier Meseure2, Isabelle Aerts4, Nathalie Cassoux5, Claude Houdayer6, François Doz7, Didier Decaudin8. 1. Laboratory of Preclinical Investigation, Translational Research Department, Paris Sciences et Lettres (PSL) University, Institut Curie, Paris, France. 2. Department of Tumor Biology, Institut Curie, Paris, France. 3. Department of Genetics, Institut Curie, Paris, France. 4. Department of Pediatric and Young Adult Oncology, Institut Curie, Paris, France. 5. Department of Surgical Oncology and Ophthalmology, Institut Curie, Paris, France. 6. Department of Genetics, Institut Curie, Paris, France 6INSERM U830, Research Centre, Institut Curie, Paris Sciences et Lettres (PSL) University, Paris, France 7Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 7. Department of Pediatric and Young Adult Oncology, Institut Curie, Paris, France 7Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 8. Laboratory of Preclinical Investigation, Translational Research Department, Paris Sciences et Lettres (PSL) University, Institut Curie, Paris, France 8Department of Medical Oncology, Institut Curie, Paris, France.
Abstract
PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.