We are interested in understanding the deregulation of transcriptional pathways in human disease and in finding small molecules to normalize these gene expression patterns. Our lab uses drug discovery technology to identify novel biological regulatory pathways and potentially therapeutic small molecules.
Our current efforts are focused on four main projects:
- Identifying and characterizing new epigenetic modulators with potential as therapeutic drugs and as research tools to discover new biology.
This is our most advanced project. We are characterizing a set of compounds we have recently identified through a cell-based assay screen, which show the ability to modulate epigenetic and transcriptional events. We are analyzing the anti-cancer activity of these small molecules in human cancer cell lines and in in-vivo mouse models. The mechanism of action of these novel drugs is also being evaluated through a variety of biochemical assays and systems approaches.
Our best hit compound to date shows potent anticancer properties against non-small cell lung cancers, and breast cancer cells, while being markedly less effective in inhibiting the growth of normal cells. This small molecule triggers histone modifications, reverses telomere position silencing effects, blocks the ability of human cancer cells to form colonies on soft agar, and slows down tumor growth in vivo. Our search for its molecular target(s) is underway and we have evidence to suggest the compound targets histone demethylases.
- Using small molecules to identify undiscovered cancer genes (both tumor suppressors and oncogenes).
Profiling human tumors to define novel molecular epigenetic targets and find new biomarkers.
We utilize a variety of biochemical and molecular biology techniques as well as bioinformatic tools and animal models of disease. The most popular experimental approaches include cell-culture models of normal and cancer tissues, drug sensitivity, and proliferation assays, QRT-PCR analysis of gene expression, purification of proteins, and in-vitro activity assays, mouse xenograft studies of drug efficacy, as well as structural studies of enzyme/drug interactions, and fluorescence microscopy. We perform some of our studies in collaboration with other labs on campus including the Minna, Mangelsdorf, Liu and Rizo-Rey labs.
4. Define and modulate the function of the three putative Jumonji histone lysine demethylases in the malaria parasite, Plasmodium falciparum.
Histone modifications play an essential role regulating gene transcription in Plasmodium falciparum throughout its complex life cycle. We focus on histone methylation in the intra-erythrocytic stage of the life cycle. Tri-methyl histone marks are required for both gene activation and silencing in the malaria parasite. Jumonji histone lysine demethylases are the only enzymes enzymatically capable of demethylating these tri-methyl marks in order to silence actively transcribed genes or activate silenced genes. P. falciparum encodes three putative genes encoding Jumonji domains. We are using genetic, biochemical, and pharmacological approaches to define the essentiality and function of these enzymes regulating transcription in malaria parasite.