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Epigenetic Therapy

Epigenetic Therapy. Jean-Pierre Issa University of Texas at MD Anderson Cancer Center. Epigenetics. Clonal and irreversible changes in gene expression that cannot be attributed to changes in DNA sequence

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Epigenetic Therapy

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  1. Epigenetic Therapy Jean-Pierre Issa University of Texas at MD Anderson Cancer Center

  2. Epigenetics • Clonal and irreversible changes in gene expression that cannot be attributed to changes in DNA sequence • Silencing refers to epigenetic loss of expression that is equivalent to an inactivating mutation

  3. Epigenetic Mechanisms • Post-transcriptional • RNAi • Transcriptional • Histone modifications • DNA methylation

  4. DNA Methylation Patterns in the Genome Most Autosomal Genes Inactive X-Chromosome / Imprinted genes

  5. ER+ ER- 8yo 60yo N T Breast Cancer Normal Colon Colon Cancer ER Methylation and Age in Normal Colon 25 20 15 % ER Methylation 10 5 0 0 10 20 30 40 50 60 70 80 90 100 Age

  6. 50 40 30 % ER Methylation 20 10 0 20 40 60 80 100 Age ER Methylation in Normal Distal Colon

  7. P14ARF Methylation in Normal Colon

  8. Methylation in Normal Tissues Most stem cells unmethylated A few highly methylated (and silenced) Most stem cells lightly methylated No or minimal silencing

  9. Epigenetic Mosaicism in Aging Tissues

  10. Epigenetic Mosaicism in Aging Tissues

  11. A Model of CpG island Methylation In Aging And Cancer No local susceptibility Methylation Center Local susceptibility + strong protection Local susceptibility + loss of protection

  12. Noise in Gene Expression Gene A Gene B Elowitz et al., Science 297(5584):1183-1186, 2002

  13. Early Embryogenesis X X Post-Implantation Cancer X Adults Aging An Epigenetic View of Life (and Death)

  14. Early Embryogenesis X X Post-Implantation Cancer X Adults Aging An Epigenetic View of Life (and Death)

  15. DNMT-I HDAC-I

  16. Epigenetic Therapy: Restoration of Gene Function

  17. Hypomethylating Cytosine Analogues

  18. DAC Phase I ‘Biologic’

  19. HDAC Inhibitors Clinical Trials • Butyrate, Phenylbutyrate • Depsipeptide • SAHA • MS-275 • Valproic acid

  20. Summary • Aging in humans is accompanied by deregulation of epigenetic mechanisms, leading to epigenetic mosaicism in stem cells • We hypothesize that epigenetic mosaicism shortens lifespan by promoting the emergence of focal proliferative disorders • Epigenetic therapy partially restores the expression and function of silenced genes • Epigenetic therapy has shown promising results in the treatment of cancer

  21. Acknowledgements • Allen Yang • Lanlan Shen • Guillermo-Garcia Manero • Hagop Kantarjian • The Leukemia Department at MDACC • Funding: NCI, SUPERGEN, DoD, George & Barbara Bush Endowment • Disclaimer: Consultant for epigenomics

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