The prognosis for malignant brain tumors (astrocytomas) remains essentially unchanged despite significant advancements in neuro-oncology and radiation therapy. Our ability to design targeted therapies for astrocytomas (gliomas) is heavily dependent upon a more complete understanding of the molecular pathogenesis of these tumors and the availability of appropriate preclinical models to test potential biological therapies. Genetic alterations in human astrocytomas differ between astrocytoma grades and involve gene products important for regulating (1) growth factor signaling pathways and (2) cell cycle progression. Studies from our laboratory have demonstrated that activation of p21-ras is a common feature of low and high- grade astrocytomas and that approximately 60 percent of GBMs harbor alterations in the rap1 signaling pathway. In addition, high-grade gliomas exhibit loss of PTEN/MMAC1 expression or epidermal growth factor receptor (EGF-R) amplification/activation, suggesting a role for these proteins in astrocytoma progression. Over the past year, we have developed transgenic mice with astrocyte-specific expression of EGF-R, EGF- RvIII and p21-ras (G12V). The B8 p2l-ras (G12V) transgenic mouse strain develops astrocytomas with a latency of 3-4 months that are histologically and biologically similar to human astrocytomas. In this proposal, we propose to employ transgenic mouse models to critically evaluate the hypothesis that abnormalities in growth factor signaling and cell cycle control genetically cooperate in the molecular pathogenesis of astrocytomas. Specifically, we wish to determine whether (1) abnormal ras and rap1 signaling in astrocytes is necessary or sufficient for astrocytoma development, (2) loss of PTEN/MMAC1 signaling or EGF-R alterations are associated with astrocytoma progression, and (3) abnormal rap1 and ras signaling in astrocytes combined with defective cell cycle control is associated with astrocytoma progression. The development and characterization of mouse models mimicking the histology and molecular pathogenesis of human astrocytomas would greatly advance our ability to treat human astrocytomas by serving as informative preclinical models to test novel therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS041097-02S1
Application #
6651889
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Finkelstein, Robert
Project Start
2001-09-01
Project End
2005-06-30
Budget Start
2002-09-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$30,000
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wei, Qingxia; Clarke, Laura; Scheidenhelm, Danielle K et al. (2006) High-grade glioma formation results from postnatal pten loss or mutant epidermal growth factor receptor expression in a transgenic mouse glioma model. Cancer Res 66:7429-37
Shannon, Patrick; Sabha, Nesrin; Lau, Nelson et al. (2005) Pathological and molecular progression of astrocytomas in a GFAP:12 V-Ha-Ras mouse astrocytoma model. Am J Pathol 167:859-67
Scheidenhelm, Danielle K; Cresswell, Jennifer; Haipek, Carrie A et al. (2005) Akt-dependent cell size regulation by the adhesion molecule on glia occurs independently of phosphatidylinositol 3-kinase and Rheb signaling. Mol Cell Biol 25:3151-62
Surace, Ezequiel I; Lusis, Eriks; Murakami, Yoshinori et al. (2004) Loss of tumor suppressor in lung cancer-1 (TSLC1) expression in meningioma correlates with increased malignancy grade and reduced patient survival. J Neuropathol Exp Neurol 63:1015-27
Fraser, Melissa M; Zhu, Xiaoyan; Kwon, Chang-Hyuk et al. (2004) Pten loss causes hypertrophy and increased proliferation of astrocytes in vivo. Cancer Res 64:7773-9
Huang, Zhi-yong; Wu, YanLi; Hedrick, Nicole et al. (2003) T-cadherin-mediated cell growth regulation involves G2 phase arrest and requires p21(CIP1/WAF1) expression. Mol Cell Biol 23:566-78
Huang, Zhi-Yong; Wu, YanLi; Burke, Stephen P et al. (2003) The 43000 growth-associated protein functions as a negative growth regulator in glioma. Cancer Res 63:2933-9
Apicelli, Anthony J; Uhlmann, Erik J; Baldwin, Rebecca L et al. (2003) Role of the Rap1 GTPase in astrocyte growth regulation. Glia 42:225-34
Ding, Hao; Shannon, Patrick; Lau, Nelson et al. (2003) Oligodendrogliomas result from the expression of an activated mutant epidermal growth factor receptor in a RAS transgenic mouse astrocytoma model. Cancer Res 63:1106-13
Lau, Nelson; Uhlmann, Erik J; Von Lintig, Friederike C et al. (2003) Rap1 activity is elevated in malignant astrocytomas independent of tuberous sclerosis complex-2 gene expression. Int J Oncol 22:195-200

Showing the most recent 10 out of 13 publications