Epigenetic-modulation in myelodysplastic syndrome – DNA methylation and histone acetylation

Epigenetic regulation is critical for gene expression.  Epigenetic pathways are frequently dysregulated in cancer, which can lead to suppression of tumor suppressor genes and expression of oncogenes.

Vidaza (Azacitidine) is a nucleoside analog of cytosine which does not undergo methylation, hence, newly synthesized DNA becomes hypomethylated.  Methylation of DNA segments (CpG sequencs near gene promoters) causes suppression of gene expression, hence, hypomethylation will lead to increased expression of genes.  Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation (Vidaza azacitidine package insert).

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The drug is approved for use in patients with myelodysplastic syndrome , a disease in which the blood stem cells (immature cells) do not become healthy red blood cells, white blood cells, or platelets. These immature blood cells, called blasts, do not work the way they should and either die in the bone marrow or soon after they go into the blood. This leaves less room for healthy white blood cells, red blood cells, and platelets to form in the bone marrow. When there are fewer healthy blood cells, infection, anemia, or easy bleeding may occur.  Driving the differentiation of immature blast cells is an effective treatment.  (See NCI Myelodysplastic Syndrome Treatments).

Mirati Therapeutics is developing another drug for myelodysplastic syndrome called mocetinostat (see MRTX_News_2014_6_17_Mirati), a selective HDAC (Histone De-ACetylase) Inhibitor of HDACs 1,2,3 and 11.  HDACs remove acetyl groups from histones, thereby putting chromatin in a configuration that favors LACK of transcription.  (HDACs do this in response to methylated CpG sequences).  The result is suppression of gene expression.  In the case of myelodysplastic syndrome, genes for differentiation of blast cells are suppressed.  HDAC inhibitors reverse this, thereby permitting the expression of differentiation genes. Combining Vidaza (an agent that results in DNA hypomethylation) and mocetinostat (an agent that blocks histone de-acetylation) then makes great sense.

[Treatment with HDAC inhibitors also makes sense for tumors with mutations in histone acetylase enzymes, seen in diffuse large B cell lymphoma and bladder cancer.]

Mirati just received Orphan Drug Designation from the FDA for mocetinostat in combination with Vidaza for myelodysplastic syndrome.  The combination is in Phase 2 studies.  Orphan Drug designation is available for conditions that affect less than 200,000 patients per year, and provides 2 additional years of market exclusivity, waiver of NDA submission fees, and tax benefits.

 

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