Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Int J Radiat Oncol Biol Phys. 2019 Mar 1;103(3):728-737. doi: 10.1016/j.ijrobp.2018.10.015. Epub 2018 Oct 23.
Craniospinal irradiation (CSI) is a crucial component of treatment for medulloblastoma (MB), a brain tumor clinically stratified into prognostically distinct molecular subgroups. Preclinical models of clinically relevant CSI offer the potential to study radiation dose and volume effects in these subgroups and to identify subgroup-specific combination adjuvant therapies, particularly for very-high-risk MB in which treatments are often unsuccessful.
The commercially available Small Animal Radiation Research Platform equipped with a motorized variable collimator was used for image-guided CSI. Mice were implanted in brain cortices with patient-derived orthotopic xenografts (PDOXs) of very-high-risk Group 3 (G3) or Sonic Hedgehog (SHH) MB and were treated with fully fractionated CSI at 2 Gy/fraction for a cumulative 36 Gy. Radiation therapy dose response effects on tumor burden and overall survival were assessed. The pattern of treatment failure was determined using bioluminescence and then confirmed histologically. Acute toxicity was appraised by body weight measurements and blood work.
We established an accurate and efficient preclinical protocol to administer CSI reproducibly to mice harboring MB. CSI improved the survival of mice bearing very-high-risk G3 or SHH MB PDOXs. However, radiation therapy dose responses across models suggested significant radio-responsiveness to conventionally fractionated CSI ≥20 Gy. CSI was well tolerated; mice had no significant changes in body weight, and acute leukopenia developed but resolved soon after therapy completion.
Our protocol for preclinical CSI delivery was effective and well tolerated, and it can be readily integrated into preclinical pipelines for MB and other central nervous system-seeding tumors.
颅脊髓照射（CSI）是治疗髓母细胞瘤（MB）的重要组成部分，MB 是一种临床上分为预后明显不同的分子亚组的脑肿瘤。具有临床相关性的 CSI 临床前模型具有研究这些亚组中放射剂量和体积效应的潜力，并确定亚组特异性联合辅助治疗方法，特别是对于治疗通常不成功的极高风险 MB。
使用配备有电动可变准直器的商业可用小动物辐射研究平台进行图像引导 CSI。将源自患者的脑皮质内的原位异种移植（PDOX）的极高风险组 3（G3）或 Sonic Hedgehog（SHH）MB 植入小鼠，并以 2Gy/分次的完全分次 CSI 治疗，累积 36Gy。评估肿瘤负荷和总生存期对放射治疗剂量的反应。通过生物发光确定治疗失败的模式，然后通过组织学确认。通过体重测量和血液检查评估急性毒性。
我们建立了一种准确且高效的临床前方案，可将 CSI 重复施用于携带 MB 的小鼠。CSI 改善了携带极高风险 G3 或 SHH MB PDOX 的小鼠的生存率。然而，跨模型的放射治疗剂量反应表明，对常规分次 CSI≥20Gy 有明显的放射反应性。CSI 耐受性良好；小鼠体重无明显变化，急性白细胞减少症在治疗完成后不久出现，但很快就会缓解。
我们的临床前 CSI 递送方案有效且耐受性良好，可轻松整合到 MB 和其他中枢神经系统播种肿瘤的临床前管道中。
