Functional evaluation of therapeutic response for a mouse model of medulloblastoma

Abstract

Medulloblastoma is an aggressive childhood cerebellar tumor. We recently reported a mouse model with conditional deletion of Patched1 gene that recapitulates many characteristics of the human medulloblastoma. Qualitative symptoms observed in the mouse model include irregular stride length, impaired cranial nerve function and decreased motor coordination and performance. In our current study, several quantitative behavioral assays including a mouse rotarod, a forced air challenge, a screen inversion test, a horizontal wire test, and stride length analysis were evaluated to determine the most sensitive and cost-effective functional assay for impaired neuromotor behavior associated with disease progression. Magnetic resonance imaging (MRI) was used to confirm and monitor tumor growth and as an anatomical biomarker for therapeutic response. Wild type mice or medulloblastoma-prone, conditional Patched1 knockout mice were observed by behavioral assays and MRI from postnatal weeks 3–6. Bortezomib treatment was administered during this period and therapeutic response was assessed using cerebellar volumes at the end of treatment. Of the behavioral tests assessed in this study, stride length analysis was best able to detect differences between tumor-prone mice and wild type mice as early as postnatal day 37 (P = 0.003). Significant differences between stride lengths of bortezomib treated and control tumor-bearing mice could be detected as early as postnatal day 42 (P = 0.020). Cerebellar volumes measured by MRI at the end of treatment validated the therapeutic effects seen by behavioral tests (P = 0.03). These findings suggest that stride length analysis may serve as one of the more sensitive and cost-effective method for assessing new therapeutic compounds in this and other preclinical model of brain tumors.