Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer Braden Cathey PCB5596 Graduate Student Presentation

Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer Contents Epigenomics: Epigenetics DNA Methyltransferase Inhibitors Histone Deacetylase Inhibitors Hypothesis Results Discussion Conclusions Future Applications Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Epigenomics: Epigenetics Study of epigenetic changes in to modify the expression of genes within an organism Epigenetics Using technology to modify gene expression Can be done by with histone modification and DNA methylation Does not change the genetic code Instead genes are turned on and off Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

DNA Methyltransferase Inhibitors Epigenetic modulators used to help express genes (DNMTis) Azacitidine: Demethylation agent Analog to nucleotide cytozine At low doses it inhibits methlytransferases causing DNA to uncoil Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Histone Deacetylase Inhibitors Allows for cell cycle completion (HDACis) Inhibits removal the acetyl groups on DNA This allows the chromatin to be read Leads to expression of genes Experimental HDACis: ITF-2357 MS275 Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer Hypothesis Using dual epigenetic therapy this research is seeking to invoke a anti-tumor response in cell lines The papers purpose is to show the effects this dual epigenetic therapy on two cell lines A549 H460 Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer Materials and Methods Cell lines and cell culture In Vivo Mouse Studies Drug Reagents Drug treatments Cell line viability assays Comparison of the two most effect cell lines an the two most effective agents Tumor size in relation to agent treatment Gene expression based on cell lines and administration of DNMTis and HDACis Interferon a/b Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer Results Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Inducing Cell Lines for Reduced Proliferation This graph shows that A549 and H460 showed proliferation under the smallest percentage of ITF Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Growth Inhibition with Aza and ITF-2357 Figures show the difference in cell growth of the two chosen lines with and without Aza+ITF-2357 Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Growth Inhibition with Aza and MS-275 Figures show the difference in cell growth of the two chosen lines with Aza+MS- 275 and without them Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Tumor Reaction to Agents Figure shows the long term reaction of the agents on H460 cells xenografts from mice Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Expression of Genes Under Treatment Conditions Figure shows the quantitation of expression of the agents on oncogenes Figure shows that the combination of Aza+ITF- 2357 downregulates oncogenes more than the genes are upregulated Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Pathways Induced by Combination Treatment Figure D shows common pathways between the tested cell lines H460 and A549 with interferon alpha/beta signaling (IFNa/b signaling) Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

IFNa/b Pathway Core-Enriched Genes Expression This figure shows the success of the agents to downregulate the gene expression in cell line H460 Yet in combination the genes are upregulated Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer Discussion Research behind this paper contains more information than presented in this presentation The results that have been presented show sufficient support of the hypothesis The process was able to identify, through testing, the best cell line to demonstrate the aptitude of dual epigenetic therapy for oncogenes Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer Conclusions The two cell lines showing the greatest affinity for success using these agents in future experiments are H460 and A549. The results prove that the best combination of agents to repress the tumor growth are ITF-2357 and Aza. This paper shows that with proper technique Histone Deacetylase Inhibitors and DNA Methyltransferase Inhibitors can be used to regulate the expression of genes the cause lung cancer Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer Future Applications This study being based on mouse models gives reason to continue onto a clinical model Human based studies are currently underway If the same model is successfully applied in human trials then the way cancer is treated may change drastically With this basic study being successful other studies may begin to broaden the range of the models effectiveness in different cancers Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer Citations Topper, M. J., Vaz, M., Chiappinelli, K. B., DeStefano Shields, C. E., Niknafs, N., Yen, R.-W. C., … Baylin, S. B. (2017). Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer. Cell, 171(6), 1284–1300.e21. http://doi.org/10.1016/j.cell.2017.10.022 Tuveson, D., Vakoc, C. (2017). Untangling the genetics from the epigenetics in pancreatic cancer metastasis. Nature Genetics volume49, pages323–324. https://www.nature.com/articles/ng.3798 Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer Questions ? Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer