Chandra Joya
University of Texas MD Anderson Cancer Center, TX
Title: Epigenetically targeted strategies for brain tumor therapy
Biography
Biography: Chandra Joya
Abstract
Glioblastoma multiforme (GBM) is the most common and most aggressive malignant brain tumor, with a five year survival rate of less than 10%. Large scale profiling studies in glioblastoma have afforded insight into the genes that are aberrantly expressed in patients, however, translating this knowledge into improved clincial outcomes remains challenging. Epigenetic enzymes control gene expression and have become popular targets for cancer therapy. In particular, inhibitors of histone deacetylases (HDACi) have been developed for clinical use but have limited activity as single agents. We designed a novel epigenetically targeted strategy based on our finding that high levels of expression of LSD1 (lysine specific demethylase 1) or KDM1A is seen in glioblastoma cells compared to normal human astrocyes, and in pateint derived GBM stem cells compared to normal neural stem cells. LSD1 cooperates with HDAC1/2 and is implicated in several cancers, and we found that histone methylation was modulated by HDACi. Inhibition of LSD1, by knockdown using short hairpin RNA, or with pharmacological inhibitors, induced apoptosis in GBM lines but not normal counterparts, indicating selectivity of this approach for malignant cells. Using FDA approved drugs that target HDACs and LSD1, vorinostat and tranylcypromine, we tested in vivo efficacy of this combination in orthotopic mouse models of GBM and found enhanced survival. RNA-Seq conducted in cell lines suggested that TP53 and TP73 may be viable biomarkers to predict response to these agents, and was validated in vivo. Taken together, our results delineate a novel therapeutic strategy for the treatment of glioblastoma.rnrn