Functional evaluation of therapeutic response for a mouse model of medulloblastoma.
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.
Samano
Aislynn K
AK
Greehey Children's Cancer Research Institute, University of Texas Health Science Center, 8403 Floyd Curl Drive, MC7784, San Antonio, TX 78229-3900, USA.
Ohshima-Hosoyama
Sachiko
S
Whitney
Thomas G
TG
Prajapati
Suresh I
SI
Kilcoyne
Aoife
A
Taniguchi
Eri
E
Morgan
William W
WW
Nelon
Laura D
LD
Lin
Ai-Ling
AL
Togao
Osamu
O
Jung
Inkyung
I
Rubin
Brian P
BP
Nowak
Brent M
BM
Duong
Timothy Q
TQ
Keller
Charles
C
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001259:Ataxia / Q000209:etiology*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004354:Drug Screening Assays, Antitumor / Q000191:economics / Q000379:methods; D020233:Gait Disorders, Neurologic / Q000209:etiology; D007794:Lameness, Animal / Q000209:etiology; D008279:Magnetic Resonance Imaging; D008527:Medulloblastoma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011597:Psychomotor Performance; D011719:Pyrazines / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D000970:Antineoplastic Agents; D001897:Boronic Acids; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011480:Protease Inhibitors; C000606240:Ptch1 protein, mouse; D011719:Pyrazines; D011956:Receptors, Cell Surface; D000069286:Bortezomib