{"id":225,"date":"2014-06-19T08:34:09","date_gmt":"2014-06-19T12:34:09","guid":{"rendered":"http:\/\/blogs.shu.edu\/cancer\/?p=225"},"modified":"2021-07-02T08:52:01","modified_gmt":"2021-07-02T12:52:01","slug":"epigenetic-modulation-in-myelodysplastic-syndrome-dna-methylation-and-histone-acetylation","status":"publish","type":"post","link":"http:\/\/blogs.shu.edu\/cancer\/2014\/06\/19\/epigenetic-modulation-in-myelodysplastic-syndrome-dna-methylation-and-histone-acetylation\/","title":{"rendered":"Epigenetic-modulation in myelodysplastic syndrome – DNA methylation and histone acetylation"},"content":{"rendered":"

Epigenetic regulation is critical for gene expression. \u00a0Epigenetic pathways are frequently dysregulated in cancer, which can lead to suppression of tumor suppressor genes and expression of oncogenes.<\/p>\n

Vidaza (Azacitidine) is a nucleoside analog of cytosine which does not undergo methylation, hence, newly synthesized DNA becomes hypomethylated. \u00a0Methylation of DNA segments (CpG sequencs near gene promoters) causes suppression of gene expression, hence, hypomethylation will lead to increased expression of genes. \u00a0Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation (Vidaza azacitidine package insert<\/a>).<\/p>\n

\"CDR526219-571\"<\/a><\/p>\n

The drug is approved for use in patients with myelodysplastic syndrome<\/a> , a disease in which\u00a0the blood stem cells (immature cells) do not become healthy red blood cells, white blood cells, or platelets. These immature blood cells, called\u00a0<\/span>blasts<\/a>, 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,\u00a0<\/span>anemia<\/a>, or easy bleeding may occur. \u00a0Driving the differentiation of immature blast cells is an effective treatment. \u00a0(See NCI Myelodysplastic Syndrome Treatments<\/a>).<\/span><\/p>\n

Mirati Therapeutics is developing another drug for myelodysplastic syndrome called mocetinostat (see\u00a0MRTX_News_2014_6_17_Mirati<\/a>), a selective HDAC (Histone De-ACetylase) Inhibitor of HDACs 1,2,3 and 11. \u00a0HDACs remove acetyl groups from histones, thereby putting chromatin in a configuration that favors LACK of transcription. \u00a0(HDACs do this in response to methylated CpG sequences). \u00a0The result is suppression of gene expression. \u00a0In the case of myelodysplastic syndrome, genes for differentiation of blast cells are suppressed. \u00a0HDAC 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.<\/p>\n

[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.]<\/p>\n

Mirati just received Orphan Drug Designation from the FDA for mocetinostat in combination with Vidaza for myelodysplastic syndrome. \u00a0The combination is in Phase 2 studies. \u00a0Orphan 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.<\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

Epigenetic regulation is critical for gene expression. \u00a0Epigenetic pathways are frequently dysregulated in cancer, which can lead to suppression of tumor suppressor genes and expression of oncogenes.<\/p>\n","protected":false},"author":2252,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[25,1],"tags":[124,120,125,121,123,122],"class_list":["post-225","post","type-post","status-publish","format-standard","hentry","category-epigenetic-regulation","category-uncategorized","tag-azacitidine","tag-dna-methylation","tag-hdac","tag-histone-acetylation","tag-mocetinstat","tag-vidaza"],"post_mailing_queue_ids":[],"_links":{"self":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/225","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/users\/2252"}],"replies":[{"embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/comments?post=225"}],"version-history":[{"count":3,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/225\/revisions"}],"predecessor-version":[{"id":5023,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/225\/revisions\/5023"}],"wp:attachment":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/media?parent=225"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/categories?post=225"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/tags?post=225"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}