Epigenetic Therapy

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Epigenetic Therapy

• Jean-Pierre Issa
• University of Texas at MD Anderson Cancer Center

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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

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Epigenetic Mechanisms

• Post-transcriptional
• RNAi
• Transcriptional
• Histone modifications
• DNA methylation

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DNA Methylation Patterns in the Genome
Most Autosomal Genes
Inactive X-Chromosome / Imprinted genes
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ER Methylation and Age in Normal Colon
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ER Methylation
10
5
0
0
10
20
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50
60
70
80
90
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Age
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ER Methylation in Normal Distal Colon
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P14ARF Methylation in Normal Colon
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Methylation in Normal Tissues
Most stem cells unmethylated A few highly
methylated (and silenced)
Most stem cells lightly methylated No or minimal
silencing
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Epigenetic Mosaicism in Aging Tissues
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Epigenetic Mosaicism in Aging Tissues
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A Model of CpG island Methylation In Aging And
Cancer
No local susceptibility
Methylation Center
Local susceptibility strong protection
Local susceptibility loss of protection
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Noise in Gene Expression
Gene A
Gene B
Elowitz et al., Science 297(5584)1183-1186, 2002
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An Epigenetic View of Life (and Death)
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An Epigenetic View of Life (and Death)
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DNMT-I
HDAC-I
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Epigenetic Therapy Restoration of Gene Function
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Hypomethylating Cytosine Analogues
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(No Transcript)
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DAC Phase I Biologic
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HDAC Inhibitors Clinical Trials

• Butyrate, Phenylbutyrate
• Depsipeptide
• SAHA
• MS-275
• Valproic acid

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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

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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