Day 1 :
University of Texas MD Anderson Cancer Center, TX
Time : 09:20-09:45
Joya Chandra, Ph.D., is an Associate Professor at the University of Texas MD Anderson Cancer Center. Research in her lab is directed towards understanding the basis for sensitivity and resistance to cancer therapeutics and optimizing their use. She has published on this topic for the past 15 years. Several of her recent publications have described the mechanism of action of epigenetically targeted agents such as histone deacetylase inhibitors, either as single agents or in combination with other therapies. She has authored over 50 original research papers, invited reviews and book chapters.
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
University of Texas, M.D. Anderson Cancer Center
Time : 09:45-10:15
Dr.Bhat,Krishna P is an Associate Professor at the University of Texas MD Anderson Cancer Center. Research in her lab is directed towards understanding the basis for sensitivity and resistance to cancer therapeutics and optimizing their use.He has published on this topic for the past 15 years. Several of his recent publications have described the mechanism of action of epigenetically targeted agents such as histone deacetylase inhibitors, either as single agents or in combination with other therapies.He has authored over 50 original research papers, invited reviews and book chapters.
In glioblastoma (GBM), Proneural (PN) and Mesenchymal (MES) cancer stem cells (CSCs) were identified as distinct subtypes with their individual progenies (non-CSCs). Here we report that following irradiation, intercellular extrinsic signals from senescent non-CSCs provoke PN CSCs’ compensatory growth, thereby resulting in persistent transcriptomic and phenotypic transformation toward more malignant MES CSCs (PN-MES transition: PMT). PMT of CSCs is accompanied with the activated wound healing pathway, which is significantly associated with poorer prognosis of GBM patients. During PMT of CSCs, a CSC marker CD133 is lost, while CDX expression evolves. These CDX-positive, but not CDX-negative GBM cells are highly tumorigenic and multipotent in vivo, suggesting CDX as a novel MES CSC marker. Inhibition of CDX attenuates clonogenicity and radioresistance. Lastly, CDX and CD133 expressions are independently instructive for poorer prognosis of MES and PN GBM, respectively. Together, irradiation to GBM tumors induces damaged non-CSC-driven PMT of CSCs developing a malignant phenotype, and CDX is a clinically relevant functional marker for MES GBM stemness.