Preclinical Modeling of Image-Guided Craniospinal Irradiation for Very-High-Risk Medulloblastoma.
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 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 to a cumulative 36 Gy. Radiation therapy dose response effects on tumor burden and overall survival were assessed. The pattern of treatment failure was determined by bioluminescence and confirmed histologically. Acute toxicity was appraised by body weight measurements and blood work.
We established an accurate, efficient preclinical protocol to reproducibly administer CSI 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, well tolerated, and can be readily integrated into preclinical pipelines for MB and other central nervous system-seeding tumors.
Smith SMC, Bianski BM, Orr BA, Harknett G, Onar-Thomas A, Gilbertson RJ, Merchant TE, Roussel MF, Tinkle CL.