Transgenic Research

, Volume 19, Issue 5, pp 829–840

Functional evaluation of therapeutic response for a mouse model of medulloblastoma

  • Aislynn K. Samano
  • Sachiko Ohshima-Hosoyama
  • Thomas G. Whitney
  • Suresh I. Prajapati
  • Aoife Kilcoyne
  • Eri Taniguchi
  • William W. Morgan
  • Laura D. Nelon
  • Ai-Ling Lin
  • Osamu Togao
  • Inkyung Jung
  • Brian P. Rubin
  • Brent M. Nowak
  • Timothy Q. Duong
  • Charles Keller
Original Paper

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.

Keywords

Medulloblastoma Genetically-engineered mouse model Brain tumor MRI Cerebellum 

Supplementary material

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Supplementary material 1 (PDF 122 kb)
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Supplementary material 2 (PDF 223 kb)
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Supplementary material 3 (PDF 299 kb)
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Supplementary material 4 (PDF 296 kb)
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Supplementary material 5 (PDF 385 kb)

References

  1. Arenkiel BR, Tvrdik P, Gaufo GO, Capecchi MR (2004) Hoxb1 functions in both motoneurons and in tissues of the periphery to establish and maintain the proper neuronal circuitry. Genes Dev 18:1539–1552CrossRefPubMedGoogle Scholar
  2. Coughenour LL, McLean JR, Parker RB (1977) A new device for the rapid measurement of impaired motor function in mice. Pharmacol Biochem Behav 6:351–353CrossRefPubMedGoogle Scholar
  3. Crawford JR, MacDonald TJ, Packer RJ (2007) Medulloblastoma in childhood: new biological advances. Lancet Neurol 6:1073–1085CrossRefPubMedGoogle Scholar
  4. Facklam M, Schoch P, Bonetti EP, Jenck F, Martin JR, Moreau JL et al (1992) Relationship between benzodiazepine receptor occupancy and functional effects in vivo of four ligands of differing intrinsic efficacies. J Pharmacol Exp Ther 261:1113–1121PubMedGoogle Scholar
  5. Fomchenko EI, Holland EC (2006) Mouse models of brain tumors and their applications in preclinical trials. Clin Cancer Res 12:5288–5297CrossRefPubMedGoogle Scholar
  6. Gilbertson RJ (2004) Medulloblastoma: signaling a change in treatment. Lancet Oncol 5:209–218CrossRefPubMedGoogle Scholar
  7. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM et al (1995) The molecular basis of Turcot’s syndrome. N Engl J Med 332:839–847CrossRefPubMedGoogle Scholar
  8. Hamm RJ, Pike BR, O’Dell DM, Lyeth BG, Jenkins LW (1994) The Rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury. J Neurotrauma 11:187–196CrossRefPubMedGoogle Scholar
  9. Hann B, Balmain A (2001) Building ‘validated’ mouse models of human cancer. Curr Opin Cell Biol 13:778–784CrossRefPubMedGoogle Scholar
  10. Lafay-Cousin L, Strother D (2009) Current treatment approaches for infants with malignant central nervous system tumors. Oncologist 14(4):433–444CrossRefPubMedGoogle Scholar
  11. Polkinghorn WR, Tarbell NJ (2007) Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nat Clin Pract Oncol 4:295–304CrossRefPubMedGoogle Scholar
  12. Sakakibara T, Xu Y, Bumpers HL, Chen FA, Bankert RB, Arredondo MA et al (1996) Growth and metastasis of surgical specimens of human breast carcinomas in SCID mice. Cancer J Sci Am 2:291–300PubMedGoogle Scholar
  13. St Clair WH, Adams JA, Bues M, Fullerton BC, La Shell S, Kooy HM et al (2004) Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int J Radiat Oncol Biol Phys 58:727–734PubMedGoogle Scholar
  14. Taniguchi E, Cho MJ, Arenkiel BR, Hansen MS, Rivera OJ, McCleish AT et al (2009) Bortezomib reverses a post-translational mechanism of tumor genesis for patched1 haploinsufficiency in medulloblastoma. Pediatr Blood Cancer 52(2):136–144CrossRefGoogle Scholar
  15. Waza M, Adachi H, Katsuno M, Minamiyama M, Sang C, Tanaka F et al (2005) 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat Med 11:1088–1095CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Aislynn K. Samano
    • 1
    • 2
  • Sachiko Ohshima-Hosoyama
    • 1
  • Thomas G. Whitney
    • 3
  • Suresh I. Prajapati
    • 1
  • Aoife Kilcoyne
    • 1
  • Eri Taniguchi
    • 1
  • William W. Morgan
    • 2
  • Laura D. Nelon
    • 1
  • Ai-Ling Lin
    • 5
  • Osamu Togao
    • 6
  • Inkyung Jung
    • 4
  • Brian P. Rubin
    • 7
  • Brent M. Nowak
    • 3
  • Timothy Q. Duong
    • 5
  • Charles Keller
    • 1
    • 2
    • 8
  1. 1.Greehey Children’s Cancer Research InstituteUniversity of Texas Health Science CenterSan AntonioUSA
  2. 2.Department of Cellular & Structural BiologyUniversity of Texas Health Science CenterSan AntonioUSA
  3. 3.Department of Mechanical EngineeringUniversity of Texas at San AntonioSan AntonioUSA
  4. 4.Department of BiostatisticsUniversity of Texas Health Science CenterSan AntonioUSA
  5. 5.Research Imaging InstituteUniversity of Texas Health Science CenterSan AntonioUSA
  6. 6.Advanced Medical and Research CenterUniversity of Texas Southwestern Medical CenterDallasUSA
  7. 7.Department of Anatomic Pathology, Cleveland ClinicTaussig Cancer Center and the Lerner Research InstituteClevelandUSA
  8. 8.Department of PediatricsUniversity of Texas Health Science CenterSan AntonioUSA

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