epigenetic therapy

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

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5

10

15

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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

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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

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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