Current Research Projects
The overarching goals of this research program are to identify genes involved in the development of cancer, to characterize the molecular mechanisms by which these genes contribute to tumorigenesis, and to assess the clinical potential of these genes as biomarkers and therapeutic targets. Studies are primarily focused on adult and pediatric brain tumors and are designed to facilitate the translation of genome-based molecular discoveries to clinical practice.
To identify genes of interest for therapeutic development, we utilize high-throughput molecular profiling techniques to quantitatively assess gene copy number and expression in image-guided surgical biopsies and model systems of brain tumors. Surgical biopsies are linked to clinical parameters such as patient outcome and therapeutic response allowing us to identify and develop molecular markers that will improve patient diagnosis and facilitate development of more rational treatment strategies. Model systems include brain tumor-derived cell cultures and serially passaged xenografts, and transgenic mouse models of brain cancer. We utilize these models to functionally dissect the molecular basis of brain cancer and to test the therapeutic potential of candidate genes identified through molecular profiling studies.
Research related to molecular therapeutics currently involves the use of inhibitory oligonucleotides such as siRNAs and anti-microRNA oligonucleotides (AMOs). Our primary targets of interest are apoptosis-suppressing genes that are amplified and/or over expressed in brain tumors since down-regulation of these gene is likely to induce apoptotic responses in tumors in which the genes are activated. To identify apoptosis suppressors from our list of candidate target genes we measure apoptotic rates in a panel of brain tumor cell lines treated with target specific and control siRNAs and AMOs. Potent inducers of apoptosis are then tested for anti-tumor efficacy in xenograft and transgenic models. We are testing a variety of strategies aimed at enhancing delivery of oligonucleotides to tumor tissue such as liposome encapsulation and convection enhanced delivery.
In addition to genome-based marker and therapy development, we are investigating the basic molecular and biological mechanisms by which microRNAs contribute to brain tumorigenesis. MicroRNAs (miRNAs) are small non-coding RNAs that regulate diverse cellular processes such as differentiation, proliferation, and apoptosis, and a number of lines of evidence implicate deregulation of miRNA expression or activity in the development of cancer. We have identified a number of recurrently deregulated microRNAs in brain tumors, which are currently under investigation in this laboratory.