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April 02, 2008

The epigenome as a therapeutic target

Epigenetics is certainly a hot topic when it comes to discussing the future of cancer therapy using biologics. For those interested, a review article was published in the NEJM last month.

It's one of the topics to be discussed at the upcoming New York Cancer Consortium (NYCC) Third Annual Developmental Therapeutics Symposium to be held May 16th here in NYC.

Basically, epigenetics is the study of variations in gene expression not due to changes in the base sequence of DNA, even though it's effect can be inherited. The most striking example is when you look at identical (monozygotic) twins. Early on in life, the genes expressed by each twin are similar. If they are raised in different environments or have different lifestyle choices e.g., diet and smoking, this expression pattern can change so that eventually one twin might be more susceptible to cancer than the other. So far the markers for this change in expression are DNA methylation and histone modification. (The histones are the protein spools around which DNA is wrapped.) Hypomethylation of DNA in colon cancer has been known since 1983.

 

Last Friday, I attended NYCC's annual review of symposia by the various cancer societies. The presenters reviewed papers studying the DNA hypomethylating agents azacytidine and decitabine which already have FDA-approval for treatment of myelodysplastic syndrome. The histone deacetylase (HDAC) inhibitor vorinostat is being tested for other uses besides cutaneous T-cell lymphoma.

Monday I was at the New York Blood Center where they hosted a conference on umbilical cord blood banking. "Ex Vivo Expansion of Cord Blood Products" was the title of the talk by Ronald Hoffman, MD who is a professor at the Mount Sinai School of Medicine and Director of Myeloproliferative Disorders Research Consortium. He talked about his efforts in trying to expand the volume of the typical umbilical cord blood unit by prompting these cells to replicate without differentiating into mature cells. Currently, it requires two units to transplant an adult who is being treated for leukemia or other blood disease. This additional unit complicates things since there has to be some matching done against the recipient's immune system.

Hoffman found that he could expand the number of stem cells, as identified by various surface markers, but they didn't work was well in engrafting in the recipient as the the primary cord blood unit. His hypothesis was that somehow the critical genes were being silenced by epigenetic factors. To counteract this, he used chromatin modifiers: a DNA hypomethylating agent and histone deacetylase inhibitor to reverse the possible silencing. He found better results in engraftment with this experimental treatment.

Once I get a chance to read more on his published results or inteview him directly, I'll be able to talk more in detail in a later post.

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