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Modeling Astrocytomas in a Family of Inducible Genetically Engineered Mice: Implications for Preclinical Cancer Drug Development

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CNS Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Astrocytomas, the most common intracranial malignancies, are a morphologically and molecularly heterogeneous group of brain tumors with potentially dismal patient outcomes for which few effective drugs are available. Genetically engineered mouse (GEM) models of astrocytoma represent a powerful technique for defining the molecular and genetic abnormalities that contribute to tumorigenesis. Based on the genetic aberrations observed in human astrocytomas, we have generated a series of conditional, inducible GEM models of astrocytomas that recapitulate the spectrum of morphological phenotypes of human astrocytomas. However, the extent to which any given GEM model recapitulates the molecular alterations in human tumors must be determined to validate its usefulness in preclinical studies. We are currently pursuing comparative evaluation of primary astrocytomas as formed in GEM and in patients to (1) examine the signaling pathway abnormalities caused by defined genetic lesions in GEM astrocytomas and (2) identify protein biomarkers that can define human astrocytomas that most closely resemble their murine counterparts. To utilize these GEM for combined preclinical evaluation of targeted therapeutic agents and biomarkers predictive of response, we have developed a panel of cell-based assays (CBA) and an orthotopic allograft model of high-grade astrocytomas using primary astrocytes derived from GEM. These tools should prove useful for preclinical drug development studies and provide a link between preclinical drug development in GEM astrocytoma models and rational design of human clinical trials involving only those patients with tumors having similar signaling pathway abnormalities.

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Authors and Affiliations

  1. Department of Pathology & Laboratory Medicine and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    C. Ryan Miller, Natalie O. Karpinich & Terry Van Dyke

  2. Mouse Cancer Genetics Program, Centers for Cancer Research and Advanced Preclinical Research, National Cancer Institute, Frederick, MD, USA

    Qian Zhang, Serguei Kozlov & Terry Van Dyke

  3. Division of Neurosurgery, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    Elizabeth Bullitt

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  1. C. Ryan Miller
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Correspondence to C. Ryan Miller .

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  1. School of Medicine, Emory University, Clifton Road 1365C, Atlanta, 30322, U.S.A.

    Erwin G. Meir

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Miller, C.R., Karpinich, N.O., Zhang, Q., Bullitt, E., Kozlov, S., Van Dyke, T. (2009). Modeling Astrocytomas in a Family of Inducible Genetically Engineered Mice: Implications for Preclinical Cancer Drug Development. In: Meir, E. (eds) CNS Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-60327-553-8_7

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  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60327-552-1

  • Online ISBN: 978-1-60327-553-8

  • eBook Packages: MedicineMedicine (R0)

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