epigenetic therapy
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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 - PowerPoint PPT PresentationTRANSCRIPT
Epigenetic Therapy
Jean-Pierre IssaUniversity 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
0
5
10
15
20
25
0 10 20 30 40 50 60 70 80 90 100
Age
% E
R M
eth
yla
tion
ER+ER- 8yo60yo N T
BreastCancer
NormalColon
Colon Cancer
ER Methylation in Normal Distal Colon
0
10
20
30
40
50
20 40 60 80 100Age
% E
R M
eth
yla
tion
P14ARF Methylation in Normal Colon
Methylation in Normal Tissues
Most stem cells unmethylatedMost stem cells unmethylatedA few highly methylatedA few highly methylated
(and silenced)(and silenced)
Most stem cells lightly Most stem cells lightly methylatedmethylated
No or minimal No or minimal silencingsilencing
Epigenetic Mosaicism in Aging Tissues
Epigenetic Mosaicism in Aging Tissues
A Model of CpG island Methylation In Aging And CancerA Model of CpG island Methylation In Aging And Cancer
No local No local susceptibilitysusceptibility
Local Local susceptibilitysusceptibility+ strong + strong protectionprotection
Local Local susceptibilitysusceptibility+ loss of + loss of protectionprotection
Methylation Center
Elowitz et al., Science 297(5584):1183-1186, 2002Elowitz et al., Science 297(5584):1183-1186, 2002
0
5
10
15
20
25
30
35
40
45
50
0 5 10 15 20 25 30 35Expression Level
% o
f ce
lls
Noise in Gene Expression
Gene A Gene B
An Epigenetic View of Life (and Death)
Early Embryogenesis
Post-Implantation
AdultsX
Aging
X XCancer
An Epigenetic View of Life (and Death)
Early Embryogenesis
Post-Implantation
AdultsX
Aging
X XCancer
HDAC-I
DNMT-I
Epigenetic Therapy: Restoration of Gene
FunctionSilenced Gene
Function Evidence of restoration of function by epigenetic therapy
ER Estrogen Receptor
Restored expression from estrogen sensitive genes
RARB2 Retinoic acid receptor
Restored growth suppression by retinoic acid
MLH1 Mismatch repair
Correction of mismatch repair defect
P16/INK4a cell-cycle regulation
Restoration of RB checkpoint
P14/ARF MDM2 inhibition
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