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.
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