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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
• Silencing refers to epigenetic loss of
expression that is equivalent to an
inactivating mutation
Epigenetic Mechanisms
• Post-transcriptional
• RNAi
• Transcriptional
• Histone modifications
• DNA methylation
DNA Methylation Patterns in the Genome
Most Autosomal Genes
Inactive X-Chromosome / Imprinted genes
ER Methylation and Age in Normal Colon
ER+ ER- 8yo 60yo
N
T
Breast Normal Colon
Cancer Colon Cancer
% ER Methylation
25
20
15
10
5
0
0
10
20
30
40
50
Age
60
70
80
90
100
ER Methylation in Normal Distal Colon
50
% ER Methylation
40
30
20
10
0
20
40
Age
60
80
100
P14ARF Methylation in Normal Colon
Methylation in Normal Tissues
Most stem cells unmethylated
A few highly methylated
(and silenced)
Most stem cells lightly
methylated
No or minimal silencing
Epigenetic Mosaicism in Aging Tissues
Epigenetic Mosaicism in Aging Tissues
A Model of CpG island Methylation In Aging And Cancer
Methylation
Center
No local
susceptibility
Local susceptibility
+ strong protection
Local susceptibility
+ loss of protection
Noise in Gene Expression
50
Gene A
45
% of cells
40
Gene B
35
30
25
20
15
10
5
0
0
5
10
15
20
Expression Level
25
30
Elowitz et al., Science 297(5584):1183-1186, 2002
35
An Epigenetic View of Life (and Death)
Early Embryogenesis
X
X
Post-Implantation
Cancer
X
Aging
Adults
An Epigenetic View of Life (and Death)
Early Embryogenesis
X
X
Post-Implantation
Cancer
X
Aging
Adults
DNMT-I
HDAC-I
Epigenetic Therapy:
Restoration of Gene Function
Silenced
Gene
Function
Evidence of restoration of function
by epigenetic therapy
ER
Estrogen
Receptor
Restored expression from estrogen
sensitive genes
RARB2
Retinoic acid Restored growth suppression by
receptor
retinoic acid
MLH1
Mismatch
repair
P16/INK4a cell-cycle
regulation
P14/ARF
MDM2
inhibition
Correction of mismatch repair
defect
Restoration of RB checkpoint
Restored normal cellular
distribution of MDM2
Hypomethylating Cytosine Analogues
DAC Phase I ‘Biologic’
Dose
N
CR+PR
Total Dose
5x10
5
2 (40%)
50
10x10
6
1 (17%)
100
15x10
17
10 (59%)
150
20x10
8
1 (13%)
200
15x15
7
1 (14%)
225
15x20
3
0 (0%)
300
75x10
17
1 (6%)
750
HDAC Inhibitors Clinical Trials
• Butyrate, Phenylbutyrate
• Depsipeptide
• SAHA
• MS-275
• Valproic acid
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
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