What are your 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.

What made you decide to pursue that type of research?

The brain and its maladies are ever mysterious but more easily treatable than they used to be, except for brain tumors whose prognosis remains infaust. Brain tumors are among the most devastating of human cancers. Their location in the pièce de résistance of human evolution and their ability to resist any contemporary treatment are equally fascinating. Despite their profound impact on the unfortunate person concerned, brain tumors are comparably neglected in research and the public remains unaware of the magnitude of this disease.

What are some of your current research projects?

Our research addresses both translational and basic questions in neuro-oncology with the ultimate goal to identify novel therapeutic approaches to treat high-grade gliomas.
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 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 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 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.

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 gene interactions, promotes gliomagenesis. Our main goal is to further characterize this landscape topologically and dynamically 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. Such relationships include the EGFR oncogene on 7p11.2 and its tyrosine phosphorylation target ANXA7, a novel tumor suppressor on 10q22.2 that may be involved in mechanisms ensuring membrane translocation during signal transduction and in attenuating EGFR signaling.

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 20 percent of gliomas.

Why did you choose Northwestern University Feinberg School of Medicine?

Neuro-oncology is on the crossroad of two of FSM’s major programmatic foci, namely cancer and neuroscience. The strength of FSM in these areas both clinically and in research, serves as an ideal fundament for establishing the predominant brain tumor center for the Midwest at Northwestern.

What is the biggest challenge you have experienced so far?

The traffic and weather in Chicago.

What do you see for the future?

Northwestern Brain Tumor Institute becoming one of the top five brain tumor centers in the US.