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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

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

9. 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

10. 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

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

12. 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

13. 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 downregulates oncogenes more than the genes are upregulated
Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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.
Tuveson, D., Vakoc, C. (2017). Untangling the genetics from the epigenetics in pancreatic cancer metastasis. Nature Genetics volume49, pages323–324.
Epigenomics: Analysis of Epigenetic Therapy to Treat Cancer

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