My primary research interests involve the molecular pathogenesis of brain tumors, particularly malignant gliomas. The efforts of my laboratory are currently directed toward both basic science and more clinically oriented translational investigations.
microRNA (miRNA) biology
We are particularly interested in the impact of miRNA-based gene regulation in the evolution of primary brain tumors. miRNAs are small noncoding RNAs that mediate pre-translational repression of selected genes by binding loosely complementary sequences in target mRNAs, most commonly in their 3’-untranslated regions. Numerous miRNAs have been implicated in neoplastic processes, including brain cancers like glioma and medulloblastoma. We initially identified the miRNA miR-26a as a direct translational repressor of the tumor suppressor PTEN. Furthermore, we demonstrated that miR-26a is amplified at the genomic level in a significant portion of high-grade gliomas and that miR-26a-mediated PTEN regulation facilitates gliomagenesis in vivo. More recently, we have been increasingly focused on characterizing miRNA networks influencing the development of lower-grade and so-called proneural glioma subtypes. In these investigations, we have shown that miR-34a and its direct target, PDGFRA, are involved in a feed-forward negative regulatory loop that promotes tumorigenesis in proneural gliomas. We are currently investigating other miRNAs involved in the potentiation of oncogenic networks and the maintenance of self-renewal capability in glioma cells of origin. Through these studies, we hope to identify pathogenic miRNA/mRNA interactions and the biological contexts in which they act, both of which may serve to facilitate therapeutic development.
As our understanding of brain tumor biology has grown, so too has the realization that each tumor class is notably heterogeneous in its molecular characteristics. Recently, large-scale genomic and transcriptomic analyses have revealed distinct subclasses of malignant glioma, each of which will most likely respond differently to rationally designed targeted therapies. From the standpoint of molecular pathology, the task now becomes to develop effective means by which to rapidly identify specific tumor subclasses and, in this way, facilitate the development and application of new drug trials. We are currently testing a variety biomarker sets using immunohistochemistry as well as direct genomic analysis. Our ultimate aim is to develop robust techniques that can be applied to formalin-fixed paraffin-embedded (FFPE) material, thus ensuring broad applicability. We also intend to perform similar molecular characterization studies on medulloblastoma and other primary brain tumors.
Large-scale molecular profiling
Leveraging the extensive tissue resources afforded by the MSKCC Brain Tumor Center and Department of Pathology, we have embarked on a series of investigations integrating genomics, transcriptomics, epigenomics, and clinical data with the aim of identifying biologically relevant disease subclasses, actionable biomarkers, and molecular targets for treatment design. This work has recently led to insights into the molecular classification of lower-grade astrocytomas, particularly with regard to establishing clinically distinct disease subclasses. We are also investigating the affects of cytotoxic therapy on the molecular evolution of malignant gliomas using next-generation sequencing technology in a matched pre- and post-treatment tumor sample set. We have also developed an array of computational tools to facilitate our analyses.