The overall goal of our research program is to identify and characterize novel epigenetic targets regulating promoting drug resistance, growth and metastasis of prostate and breast cancers. Specifically, the first step is to delineate how histone modifications interact with other chromatin components to modulate distinct transcription programs in cancer and cancer stem cells (or tumor progenitor populations) to promote treatment resistance, ensure survival and effectively evade the cell death. Based on this fundamental knowledge the second step is to develop targeted therapies for these reversible modifications in the form of small molecule inhibitors.
Project 1: Based on the premise that metastatic prostate cancer is a cancer of the epigenome, our lab is geared to use a multi-faceted approach, combining drug discovery with tumor biology to delineate the mechanism of action of the epigenetic regulators. Working in collaboration with Dr. Lawrence and Dr. Schonbrunn laboratory, we have recently identified several small molecule inhibitors with potent in vitro inhibitory activity and anti-tumor activities (Lawrence H, Mahajan K et. al., J Med Chem, 2015). Our laboratory will characterize the efficacy and potency of the novel BET bromodomain and tyrosine kinase inhibitors using tamoxifen-resistant breast tumor models and metastatic prostate cancer models, to advance them as novel therapeutics for breast cancer and prostate cancer.
Project 2: Chromatin replication, the coordinate doubling of DNA and histones during each cell division, is a tightly regulated process, and represents one of the most vulnerable stages in cell cycle. Improper chromatin duplication in normal cells results in insidious genome instability and is manifested as cancer and developmental disorders. Conversely, targeted inhibition of proteins regulating chromatin duplication is often utilized as a strategy to induce mitotic catastrophe to eradicate proliferating cancer cells. Our recent discovery that WEE1 kinase directly phosphorylates, the core histone H2B at tyrosine 37(Y37), provides novel insights into pathways regulating chromatin duplication. Our lab will investigate the role of WEE1 epigenetic activity in cancer stem cell biology.