GENETIC PATHWAYS TOWARD GLIOMAGENESIS

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DESCRIPTION (Applicant's Description): Patients with de novo glioblastoma multiforme have a median survival of nine months when treated with currently available therapy. Although the prognosis for low-grade astrocytomas is significantly better, in at least 50 percent of cases, these tumors will progress to intermediate-grade (anaplastic) astrocytomas and finally to glioblastoma multiforme. Progress in the understanding of the pathogenesis of these deadly brain tumors has been hampered by the lack of a bonafide animal model that recapitulates the genetics and biology of this disease. Cytogenetic analysis of clinical glioma specimens has identified multiple genetic lesions known to be involved in oncogenic/tumor suppressor pathways. The working hypothesis of the applicant is that distinct genetic pathways govern the development of the two clinical subtypes of glioblastoma. Those that develop from low- or intermediate-grade astrocytomas accumulate mutations over time in key pathways involved in growth, differentiation, apoptosis and angiogenesis, producing progressively more aggressive phenotypes. In contrast, de novo glioblastomas arise as a consequence of a critical combination of mutations in which the initial phenotype is the highest grade tumor. The DePinho laboratory has engineered and extensively characterized strains of mice with deletions of several of the genes which likely participate in the pathogenesis of these distinct disease entities. The availability of these mice coupled with the laboratory's expertise in transgenic and knockout technology, provides the applicant with a unique opportunity to probe the genetic mechanisms of gliomagenesis, develop a spontaneous mouse model of glioblastoma, and gain conceptual and technical experience in these areas. Aim 1: To generate a transgenic mouse that expresses fluorescently-labeled intermediate filaments, GFAP and nestin, to be used as specific markers of astrocytes and stem cells, respectively, in all experiments. Aim 2: To assess the role of overexpression of the oncogene, EGFR, in the pathogenesis of glioblastoma. Aim 3: To study the biological effects of known mutations in key tumor suppressor pathways governing growth, differentiation and survival of glial cells and how such mutations functionally interact with activated EGFR. Aim 4: To identify genes that cooperate with known oncogenes and tumor suppressors in the development and/or progression of malignant gliomas using a well-established retroviral insertional approach.