Department of Clinical Sciences, Centre de Recherche en Cancérologie UMR Inserm U1052-Equipe 11- CLB - Lyon, France.
PLoS One. 2012;7(6):e32458. doi: 10.1371/journal.pone.0032458. Epub 2012 Jun 27.
Chondrosarcomas are the second most frequent primary malignant type of bone tumor. No effective systemic treatment has been identified in advanced or adjuvant phases for chondrosarcoma. The aim of the present study was to determine the antitumor effects of doxorubicin and everolimus, an mTOR inhibitor on chondrosarcoma progression.
Doxorubin and/or everolimus were tested in vivo as single agent or in combination in the rat orthotopic Schwarm chondrosarcoma model, in macroscopic phase, as well as with microscopic residual disease. Response to everolimus and/or doxorubicin was evaluated using chondrosarcoma volume evolution (MRI). Histological response was evaluated with % of tumor necrosis, tumor proliferation index, metabolism quantification analysis between the treated and control groups. Statistical analyses were performed using chi square, Fishers exact test. Doxorubicin single agent has no effect of tumor growth as compared to no treatment; conversely, everolimus single agent significantly inhibited tumor progression in macroscopic tumors with no synergistic additive effect with doxorubicin. Everolimus inhibited chondrosarcoma proliferation as evaluated by Ki67 expression did not induce the apoptosis of tumor cells; everolimus reduced Glut1 and 4EBP1 expression. Importantly when given in rats with microscopic residual diseases, in a pseudo neoadjuvant setting, following R1 resection of the implanted tumor, everolimus significantly delayed or prevented tumor recurrence.
MTOR inhibitor everolimus blocks cell proliferation, Glut1 expression and HIF1a expression, and prevents in vivo chondrosarcoma tumor progression in both macroscopic and in adjuvant phase post R1 resection. Taken together, our preclinical data indicate that mTOR inhibitor may be effective as a single agent in treating chondrosarcoma patients. A clinical trial evaluating mTOr inhibitor as neo-adjuvant and adjuvant therapy in chondrosarcoma patients is being constructed.
软骨肉瘤是第二常见的原发性恶性骨肿瘤。在晚期或辅助阶段，尚未发现针对软骨肉瘤的有效全身治疗方法。本研究旨在确定阿霉素和依维莫司（mTOR 抑制剂）对软骨肉瘤进展的抗肿瘤作用。
在大鼠原位 Schwarm 软骨肉瘤模型中，以单药或联合用药的形式，在宏观阶段以及微观残留疾病阶段，测试阿霉素和/或依维莫司。通过软骨肉瘤体积演变（MRI）评估依维莫司和/或阿霉素的反应。用肿瘤坏死百分比、肿瘤增殖指数、处理组和对照组之间的代谢定量分析来评估组织学反应。使用卡方检验、Fisher 确切检验进行统计分析。与未治疗相比，阿霉素单药对肿瘤生长没有影响；相反，依维莫司单药显著抑制了宏观肿瘤的肿瘤进展，与阿霉素无协同增效作用。依维莫司通过 Ki67 表达抑制软骨肉瘤增殖，不会诱导肿瘤细胞凋亡；依维莫司降低了 Glut1 和 4EBP1 的表达。重要的是，当在植入肿瘤 R1 切除后的微观残留疾病大鼠中，在假新辅助治疗环境中给予依维莫司时，它显著延迟或防止了肿瘤复发。
mTOR 抑制剂依维莫司阻断细胞增殖、Glut1 表达和 HIF1a 表达，并在宏观和 R1 切除后的辅助阶段防止体内软骨肉瘤肿瘤进展。综上所述，我们的临床前数据表明，mTOR 抑制剂可能作为单一药物有效治疗软骨肉瘤患者。正在构建一项评估 mTOR 抑制剂作为软骨肉瘤患者新辅助和辅助治疗的临床试验。
