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Preclinical Testing of Tandutinib in a Transgenic Medulloblastoma Mouse Model

Ohshima-Hosoyama, Sachiko MD, PhD; Davare, Monika A. PhD; Prajapati, Suresh I. MSc; Abraham, Jinu PhD; Lal, Sangeet PhD; Nelon, Laura D. BSc; Kilcoyne, Aoife MD; Giles, Francis J. MD; Hanes, Martha A. DVM; Rubin, Brian P. MD, PhD; Keller, Charles MD

Journal of Pediatric Hematology/Oncology: March 2012 - Volume 34 - Issue 2 - p 116–121
doi: 10.1097/MPH.0b013e3182309fe4
Original Articles

Overexpression of platelet-derived growth factor receptor alpha (PDGFR-A) has been documented in association with primary tumors and metastasis in medulloblastoma. Tumors from our genetically engineered sonic hedgehog-driven medulloblastoma mouse model overexpress PDGFR-A in primary tumors and thus this mouse model is a good platform with which to study the role of PDGFR-A in this central nervous system malignancy. We hypothesized that inhibition of PDGFR-A in medulloblastoma can slow or inhibit tumor progression in living individuals. To test our hypothesis, we targeted PDGFR-A mediated tumor growth in vitro and in vivo using the tyrosine kinase inhibitor, tandutinib (MLN-518), which strongly inhibits PDGFR-A. Although PDGFR-A inhibition by this agent resulted in reduced mouse tumor cell growth and increased apoptosis in vitro, and reduced tumor cell proliferation in vivo, tandutinib did reduce tumor volume at the doses tested (360 mg/kg) in vivo. Thus, tandutinib may be an agent of interest for sonic hedgehog-driven medulloblastoma if a synergistic drug combination can be identified.

*Greehey Children’s Cancer Research Institute

Departments of Medicine

§Lab Animal Resources, University of Texas Health Science Center, San Antonio, TX

Department of Anatomic Pathology, Cleveland Clinic, Taussig Cancer Center and the Lerner Research Institute, Cleveland, OH

Pediatric Cancer Biology Program, Pape' Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR

Sachiko Ohshima-Hosoyama, Monika A. Davare have contributed equally.

Supported in full by an $8600 Grant from the Rally Foundation in honor of Matthew Butterfield to the Pediatric Preclinical Testing Initiative.

C.K. received a honorarium to present at Research & Development grand rounds at Millennium Pharmaceuticals (a Takeda company). C.K. is a cofounder of Numira Biosciences, a preclinical imaging biotechnology company.

The other authors declare no conflict of interest.

Reprints: Charles Keller, MD, Pediatric Cancer Biology Program, Pape' Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Mail Code: L321, Portland, OR 97239-3098. (e-mail keller@ohsu.edu).

Received September 22, 2010

Accepted June 7, 2011

Copyright © 2012 Wolters Kluwer Health, Inc. All rights reserved.