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Home > Neurosurgery Research > BTRC > Haas-Kogan Laboratory  
Haas-Kogan Laboratory
Principal Investigator: Daphne Haas-Kogan MD
Current Research Projects
The Role of Apoptosis and Genetic Mutations in the Pathogenesis, Treatment and Outcome of Children with Brain Tumors
Principal Investigator: Daphne Haas-Kogan MD
The project funded by the National Institutes of Health CAP Award proposes to identify genes important in p53-independent radiation-induced apoptosis. We have focused on a cell line, SF188, derived from a pediatric patient with glioblastoma multiforme (GM) and expressing mutant p53. In contrast to other GM-derived cell lines that exhibit marked resistance to radiation-induced apoptosis, SF188 undergoes extensive apoptosis in response to ionizing radiation. We sought to identify genes required for p53-independent apoptosis by identifying and isolating transcripts differentially expressed in irradiated and unirradiated SF188 cells. Using a cDNA expression array, TRADD was identified as a transcript induced by radiation in SF188 cells but not in primary human astrocytes. Transcriptional-activation of TRADD is a novel mode of TRADD regulation and apoptosis induction. Furthermore, exogenously expressed TRADD in SF188 further sensitizes the cells to radiation and chemotherapy-induced apoptosis. To generalize our findings, TRADD was introduced into additional GM cell lines by using retroviral tranduction or a mammalian expression vector. In all the GM cell lines tested TRADD induces apoptosis, suggesting that TRADD may be a promising target for gene therapy (Yount et al.: Oncogene 2001; 20:2826-2835).
Program for the Treatment of Malignant Brain Tumors, Project 4: Enhancing the Responsiveness of Astrocytic Tumors to Therapeutic Irradiation
Principal Investigator: Daphne Haas-Kogan MD
Co-Investigators: Dennis F. Deen PhD and Mark A. Israel MD
Studying the response of brain tumor-derived cell lines to irradiation, we found that medulloblastoma-derived lines responded to irradiation with rapid, extensive, p53-dependent apoptosisÑalthough glioblastoma-derived lines do not. Our research seeks to extend these observations to learn more about the precise molecular mechanism which inhibit the induction of apoptosis in glioblastoma-derived cell lines. We also seek to understand the mechanism by which p53 expression affects the clonogenic survival of glioblastoma cells which do not undergo apoptosis. Through interactions with other Projects we will also 1) explore the possibility of developing tumor markers that might be useful for improving the management of brain tumor patients, and 2) examine novel therapeutic possibilities that might be developed to improve therapy. In these experiments, we will examine the possibilities that p53 mutations, spontaneously occurring apoptosis, and the susceptibility of tumor cells to undergo apoptosis might be highly associated with the response of astrocytic tumors in irradiation. We will attempt to examine these variables in comparable groups of patients who have received radiation therapy that was administered in different fractionation schema.
The Role of PTEN Mutations in the Behavior of Malignant Glioma Tumors
Principal Investigator: Daphne Haas-Kogan MD
The most common genetic alteration in GM tumors is loss of heterozygosity of chromosome 10q, which is seen in approximately 90% of tumors. PTEN is a tumor-suppressor gene that maps to chromosome 10q23. It is mutated in GM tumors as well as in a myriad of additional human malignancies. We have recently reported that PTEN regulates the activity of the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) pathway, a signaling cascade implicated in cancer development. PTEN mutations in GM cell lines lead to increased, dysregulated PKB/Akt activity. Since PTEN mutations have been identified in a myriad of human malignancies, including 30-45% of GM tumors, our data implicate dysregulation of the PI3K/PKB pathway as a key mediator of human carcinogenesis. The proposed work seeks to define how PTEN mutations contribute to the pathogenesis of GM tumors and to explore the therapeutic potential of gene-therapy approaches designed to target the dysregulated PI3K/PKB pathway. Specifically, we will examine primary human brain tumors for increased PKB/Akt activity and ask whether such increased activity is due to PTEN mutations. In addition, we will assess whether PTEN mutations and the resultant activation of PKB correlate with clinical outcome in patients with GMs. Dysregulation of the PI3K/PKB cascade in a large proportion of GM tumors establishes this pathway as an important target for therapeutic intervention. Therefore, we plan to evaluate the in vivo antineoplastic activity of therapies designed to inhibit the PKB signal transduction pathway. These studies may permit us to use PTEN and the PI3K/PKB signal transduction cascade as a molecular point of intervention in the treatment of GM tumors.
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