New Therapeutic Targets in Cancer
Transcript of 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