New Therapeutic Targets in Cancer

8/2/2019 New Therapeutic Targets in Cancer

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New therapeutic targets incancer: the epigeneticconnection

Caitlin Roush and Gaby Ochoa


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Background:

Epigenetics based on inheritance ofinformation

Heritable

Different components comprise the safetyof the epigenome


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Chromatin Organization

Plays an important role in gene expression

Modifying the tertiary structure to an open

or accessible (euchromatin status)

Close and inaccessible configuration

(heterochromatin)


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Remodeling Chromatin Covalent modification Acetylation

Methylation Ubiquitination Phosporylation Biotinulation Sumoylation

Intrinsic DNA modification

Exchange

Disrupting DNA


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Methylation

Covalent addition of a methyl group

Involves flipping the target cytosine

Catalyzed by methyltransferase (DNMTs)

Normal development

Abnormal methylation patterns

Correlation between methylation andhistone modification


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Epigenetics: Cancer

Developed by de novo methylations

Detections

Hypermethylation

LOH or homozygous Deletions


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DNA methylation

Abnormal methylation in the CpG containpromoters of genes correlated with

silencing

Normal

Not methylated

Cancer cells

Hypermethylation occurs


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Histone Acetylation Positive charge on unacetylated lysines in the

histones is attracted to the negativelycharged DNA molecule producing compactchromatin state that is repressive fortranscription

Acetylation of the lysines removes theirpositive charge and results in an openchromatin structure

Histone deacetylase (HDAC ) remove theacetyl groups from lysine, which reverses thisprocess and silences gene expression


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Histone Methylation

Methylation of histones is also implicatedin changes in chromatin structure and

gene regulation.


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Epigenetic Therapy of Cancer

Tumorigenesis is known to be a multistepprocess in which defects in various cancer

genes accumulate. It is now clear that genetic alterations in

human cancers do not provide sufficientinformation on genomic alterations behindtumor development,progression or metastasis.

Epigeneticalso influences cancer and hasencouraged the development of newtherapies


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Inhibitors of DNA Methylation

First molecules to appear in the market

Decrease global methylation and de-

methylation of tumor suppressor-promoter-CpG islands cancer cells

Restore normal expression levels andnormal phenotypes

5-Azacytidine,5-Aza-2-deoxycytidine,Zebularine andprocainamide


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DNA methylation inhibitors asTherapy

Inhibit DNA methytransferases and causeglobal hypomethylation

High doses seem to have toxic effects onnormal cells

Haemopoietic disorders such asmyelodysplastic syndrome and myeloid

leukaemia


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HDAC is as therapeuticmolecules

HDAC have the ability to activate a subset of

genes that can produce cell cycle

arrest,induce differentiation or apoptosis intumor cells.

Natural or synthetic molecules

Hydroxamates and Trichostatin A

The mechanism of genetic silencing by HDACare associated with activation of selected

genes which repress tumor growth

New Therapeutic Targets in Cancer

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