Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Frederick National Laboratory for Cancer Research in the Comparative Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Clin Cancer Res. 2021 Jun 1;27(11):3005-3016. doi: 10.1158/1078-0432.CCR-21-0315. Epub 2021 Mar 22.
The mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression.
A total of 324 pet dogs diagnosed with treatment-naïve appendicular osteosarcoma were randomized into a two-arm, multicenter, parallel superiority trial whereby dogs received amputation of the affected limb, followed by adjuvant carboplatin chemotherapy ± oral sirolimus therapy. The primary outcome measure was disease-free interval (DFI), as assessed by serial physical and radiologic detection of emergent macroscopic metastases; secondary outcomes included overall 1- and 2-year survival rates, and sirolimus pharmacokinetic variables and their correlative relationship to adverse events and clinical outcomes.
There was no significant difference in the median DFI or overall survival between the two arms of this trial; the median DFI and survival for standard-of-care (SOC; defined as amputation and carboplatin therapy) dogs was 180 days [95% confidence interval (CI), 144-237] and 282 days (95% CI, 224-383) and for SOC + sirolimus dogs, it was 204 days (95% CI, 157-217) and 280 days (95% CI, 252-332), respectively.
In a population of pet dogs nongenomically segmented for predicted mTOR inhibition response, sequentially administered adjuvant sirolimus, although well tolerated when added to a backbone of therapy, did not extend DFI or survival in dogs with appendicular osteosarcoma.
mTOR 通路已被确定为参与高级骨肉瘤转移进展的关键营养信号枢纽。通过使用西罗莫司抑制 mTOR 信号是可行的生物学方法，并且可能减缓远处转移的生长。在这项研究中，利用患有附肢骨肉瘤的宠物狗作为儿科骨肉瘤的高价值生物模型，评估 mTOR 抑制作为减轻转移性疾病进展的治疗策略。
总共 324 只被诊断患有治疗初发附肢骨肉瘤的宠物狗被随机分为两组，进行双臂、多中心、平行优势试验，其中狗接受受影响肢体的截肢术，然后接受辅助卡铂化疗±口服西罗莫司治疗。主要终点是无病间隔（DFI），通过连续的物理和放射学检测新出现的宏观转移来评估；次要终点包括总 1 年和 2 年生存率，以及西罗莫司药代动力学变量及其与不良事件和临床结果的相关性。
该试验两组之间的中位 DFI 或总生存率没有显著差异；标准治疗（SOC；定义为截肢和卡铂治疗）狗的中位 DFI 和生存时间为 180 天[95%置信区间（CI），144-237]和 282 天（95%CI，224-383），SOC+西罗莫司狗的中位 DFI 和生存时间分别为 204 天（95%CI，157-217）和 280 天（95%CI，252-332）。
在一组未进行基因组分割预测 mTOR 抑制反应的宠物狗中，序贯给予辅助西罗莫司，尽管与治疗基础一起使用时耐受性良好，但并未延长患有附肢骨肉瘤的狗的 DFI 或生存时间。
