GIST Support Wiki31 Mar 2007
There is a new exciting trial that will be opening up soon for GIST at MSKCC combining "SAHA" Suberoylanilide Hydroxamic Acid" ( a histone deacetylase inhibitor-a very exciting new class of anti cancer molecular therapy, previously mentioned here) with Flavopiridol. They both show potent anti-KIT activity in vitro.
31 Mar 2007
Subject: SAHA Histones
Thanks for sharing! Histone deacetylase inhibitors are a major evolving strategy for anticancer drugs.
Here is the trial protocol for the SAHA flavorpiridol combination: http://clinicaltrials.gov/ct/show/NCT00324480?order=3D11
For everyone else, what the heck is a histone?
Wikipedia has a simple article about histones. http://en.wikipedia.org/wiki/Histone
Histone proteins are "molecular" spools that winds up the long string of = DNA into something compact. DNA is such a long molecule that it would not fit into a cell unless it is packaged in a very condensed form. Consider the analogy of thread wrapped around a wooden spool. In fact, you can indeed "spool DNA" around a tooth pick and see it.
Histones are much more sophisticated than a wooden spool. Histones can be reversibly modified in various ways to fine tune how tightly they condense the DNA. Histones have a lot of postive chemical charges allowing them to interact tightly with the negative chemical backbone of DNA. If the positive charges on histones are masked by chemical modification (aceytlation) then this diminishes their positive charges and consequencly reduces how tightly the histones interact with the DNA.
If the DNA is wound up tightly--or "locked down", then that affects how frequently the genes can be openned up and accessed for use. You can add the acetylation to a histone to weaken its interactions with DNA or remove the aceylation with an enzyme called histone deacetylase, which would restore the positive charge on the histone and consequently its tight binding on the DNA. Histone deacetylase inhibitors block the cell's ability to reverse the acetylation modification of the histones. The histones have less affinity to tightly wind the DNA. THis "skewing" of histone affinity by the inhibitor drug can change the patterns of gene expression in a cell context manner. Some genes are used more and some are used less. In some cases inhibitors that keep the histones stuck in their acetylated state helps to produce greater expression of the genes that "brake" the growth of cancer.
Perhaps a deacetylase inhibitor would also fit into Dr. Deunsing's findings about the histone H2ax leaving the nucleus and entering the cytoplasm to spur the death of GIST cells. Perhaps a deacetyalse inhibitor would impact this phenonmen.