Dysregulation of Nuclear Factor-kB in High-Grade Gliomas Mounting evidence suggests a major role of cell death and survival pathways in the treatment resistance of high-grade gliomas. The molecular mechanisms deciding whether a tumor cell commits to cell death or survives under therapy are complex and under fine regulation. Nuclear factor-kB (NF-kB) is a eukaryotic transcription factor on the crossroad of a cell’s decision to live or die. NF-kB is excessively activated under several pathological cell conditions, including cells that resist treatment. The primary mechanism of NF-kB-mediated resistance is the ability of the cells to escape programmed cell death. Escape from apoptosis is a common pro-survival mechanism induced by genotoxic stress that could affect all major therapeutic regimens considered standard of care in high-grade gliomas, including chemotherapy with O6-alkylating agents and radiation therapy. Although various routes can lead to NF-kB activation, evidence suggests that the so-called canonical pathway is predominantly involved in high-grade gliomas. Canonical NF-kB activation involves divergent signaling cascades that ultimately converge to activate the inhibitor of kB kinase (IKK) signalosome. While the mechanisms of NF-kB activation have been well studied, the mechanisms by which NF-kB is regulated are less well understood. | |
| We have identified several networking endogenous modulators of NF-kB activation that affect cell resistance and patient outcomes in high-grade gliomas. We have confirmed the power of those modulators to predict the outcome of high-grade glioma patients in several independent validation cohorts from different academic institutions. |  |
We are currently studying the modulator network as a means to facilitate the development and testing of new response of high- grade gliomas to adjuvant therapy. Two of our goals are to explore this network mechanistically and to develop novel molecular based therapies that target critical molecules within the network. Because NF-kB and its regulatory network are on the crossroad of a cell’s decision to live or die in response to DNA damage caused both by chemotherapy and irradiation, the development and implementation of such targeted sensitization strategies is of high relevance for combined modality treatments of high-grade gliomas. | |
Nonrandom Selection of a Cooperative Genetic Landscape During Glioma Evolution | |
| Another area of our research focuses on nonrandom chromosomal abnormalities in gliomas. Research at large has mainly focused on target genes within individual chromosomal aberrations with regard to their putative tumor-promoting or -suppressive function in brain tumors. However, these aberrations do not exist in isolation; rather there may be mechanistic links to genes at other, coincident aberrations. Because somatic evolution naturally selects “self-interested” cells that are adept at surviving, such genetic coincidence might affect function, presumably giving an advantage to glioma cells. By linking network modeling of high-dimensional DNA and RNA data to the known functional interactions of orthologous mammalian genes, we have described a nonrandom genetic landscape that, through its facilitation of altered gene interactions, promotes gliomagenesis. Our main goal is to further characterize this landscape topologically and dynamically as well as individual gene relationships as a means to identify new leads for targeted therapies for high-grade gliomas. Molecular targeting of networking landscape genes with cooperative functional relationships holds potential to achieve synergistic treatment effects by disrupting a higher-gated tumorigenic circuit driving glioma evolution. One such relationship includes the EGFR oncogene on chromosome 7p11.2 and a tyrosine phosphorylation target of EGFR on chromosome 10q. This target gene, which codes for a calcium-activated membrane-binding GTPase, is a novel tumor suppressor potentially involved in mechanisms ensuring membrane translocation and in attenuating EGFR signaling. Phosphorylation of this gene by EGFR may modulate one or more of its proposed physiological functions, possibly rendering it more susceptible to proteolysis and disrupting its interaction with other lipid or protein components. We have shown this gene to be significantly affected in its expression (and potentially its posttranscriptional regulation) by the frequent mono-allelic loss of 10q in glioblastomas. We are currently exploring the mechanism of dergulation of this gene in glioblastomas, its mechanism of interaction with EGFR, and the potential value of combined targeting of both genes in these tumors as a new therapeutic avenue. | |
Identifying Novel Tumor Suppressor Genes in Human Gliomas | |
We were first in using cDNA microarray-based comparative genomic hybridization to map genome-wide alterations in gene dosage in human gliomas.We have shown that such high-resolution mapping can precisely localize and size tumor regions where gene dosage change recurs. This research has identified novel common minimally deleted regions that involve genes assumed to be tumor suppressors such as the TOPORS gene on the long arm of chromosome 9. We are also part of a team of researchers that has pinpointed CHD5 as a novel tumor suppressor on the long arm of chromosome 1 (1p36). We have led efforts to translate the findings in mice to human tumors and have shown this gene to be altered in about 20percent of gliomas. | |
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