https://www.ncbi.nlm.nih.gov/pubmed/30184215 (pubmed abstract)
click here for full study via sci-hub
In a mouse model of IDH1-mutant brain tumors, 5-azacytidine alone improved mouse survival, and the addition of 5-azacytidine to temozolomide significantly improved survival compared to temozolomide alone.
5-azacytidine is a hypomethylating (or demethylating) agent approved and commonly used to treat acute myeloid leukemia and myelodysplastic syndrome.
IDH1-mutant gliomas are characterized by pathologically hypermethylated DNA (throughout the genome, not just at the MGMT promoter). This led to the idea that treatment with DNA demethylating agents (5-azacytidine or decitabine) would be therapeutic for IDH1-mutant gliomas. A theoretical concern with this strategy, is that these DNA demethylating agents could reduce methylation levels at the MGMT promoter and desensitize the tumors to temozolomide. The data provided in this study shows no desensitization to TMZ following treatment with 5-azacytidine, although the studies of drug sequence shown in figure 5C show temozolomide followed by 5-azacytidine as more effective than 5-azacytidine followed by temozolomide.
ReplyDeleteFinally somebody is getting around to testing this in a clinical trial.
ReplyDeleteTreatment With Azacitidine of Recurrent Gliomas With IDH1/2 Mutation
https://clinicaltrials.gov/ct2/show/NCT03666559
It's been a 5 year wait to see a trial like this.
But it seems without TMZ :| on the graph above, only 5-Aza led to modest improvement of mouse survival. A first step nonetheless.
DeleteThis is true, but mice have much smaller craniums and so cannot live nearly as long with a brain tumor as humans do. This is important when it comes to a therapy such as 5-azacytidine, which takes plenty of time to take full effect.
DeleteIn one of the previous studies, ( https://www.ncbi.nlm.nih.gov/pubmed/24077805 ) because of the short survival of mice with tumors, they harvested the tumors when the tumors got too large and passaged them into a new group of mice, in order to continue the treatment longer (see figure 5). It was only during the third passage (after 14 weeks of treatment) that the tumors started to regress.
The survival curves in the graph in my original post start to separate at about day 100 (control versus 5-aza alone). So it may require about 14 weeks or 100 days to really take effect, but if the mice don't live that long they will not benefit as much.
This trial is testing a mutant IDH1 inhibitor with and without 5-azacytidine:
ReplyDeletehttps://clinicaltrials.gov/ct2/show/NCT03684811