Markus Bredel, MD, PhD
Assistant Professor
Department of Neurological Surgery
Director, Northwestern Brain Tumor Institute Research Program
To Contact Dr. Bredel:
303 E. Superior Street, Lurie 6-111
phone: 312-503-1727
e-mail: m-bredel@northwestern.edu
Dr. Bredel's Website: www.bredel.northwestern.edu
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Research Interests
Our research is dedicated to bring molecular advances in the pathogenesis and therapy of human brain tumors to clinical application. Our laboratory aims to identify new therapeutic leads for patients with high-grade gliomas and to develop tools that allow predicting an individual patient’s likelihood to benefit from a certain treatment regimen. Our work integrates complex molecular tumor data generated by the complementary and iterative application of data-driven (genome-wide analysis) and hypothesis-driven research approaches and corresponding clinical patient profiles.
At the heart of our work is the belief that a glioma cell’s behavior and its response to therapy are contextual attributes of distinct patterns of orchestrated activity and spatiotemporal interactions between multiple genes in multifaceted pathways and networks. Our research has succeeded in prioritizing so-called hub genes whose role may be to determine network behavior and in identifying lead molecules that may factor in the susceptibility of gliomas to therapy.
We have discovered that the TNFAIP3 gene is a molecular determinant of glioblastomas’ resistance to alkylating drug therapies such as temozolomide. This gene is part of a complex network of endogenous modulators that act upon nuclear factor-kB, a eukaryotic transcription regulator that promotes cell survival. We have identified several networking endogenous modulators of nuclear factor-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 four independent validation cohorts from different academic institutions.
We were first in using cDNA microarray-based comparative genomic hybridization to map genome-wide alterations in gene dosage in 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.
Another area of our research focuses on nonrandom chromosomal abnormalities in gliomas. 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 gene interactions, promotes gliomagenesis. This landscape serves now as a unique, target-rich environment for the exploration of novel therapeutic approaches to treat high-grade gliomas.
As reported in Cell in February 2007, we are 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 20 percent of human gliomas.
Our current and future work builds up on our previous accomplishments. It applies and integrates data-driven and hypothesis-driven research to translational and basic questions in neuro-oncology. We are particularly interested to further elucidate our network of endogenous nuclear factor-kB modulators as a means to facilitate the development and testing of new strategies to predict and ameliorate the 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 nuclear factor-kB and its regulatory network have a role in a cell’s response to DNA damage caused by both chemotherapy and irradiation, the development and implementation of such targeted sensitization strategies for the treatment of high-grade gliomas is of high relevance for combined modality treatments. Another goal of our laboratory is to further characterize our genetic landscape topologically and dynamically using high-dimensional genetic, epigenetic and gene product profiling and functional validation as a means to identify new leads for targeted therapies for high-grade gliomas. Research has mainly focused on target genes within individual chromosomal aberrations with regard to their putative tumor-promoting or -suppressive function in brain tumors, rather than their mechanistic link to genes at other, coincident aberrations. 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.