Histone deacetylase inhibitors (HDACi)

I find a lot of information that histone deacetylase inhibitors (Trichostatin A (TSA), Vorinostat, 7-ureido-N-hydroxyheptanamide derivative (CKD5)) have potent anti-cancer effects in glioblastoma.

2017 https://www.ncbi.nlm.nih.gov/pubmed/27852054
"Our results demonstrate that the novel HDACI CKD5 is a promising therapeutic candidate for glioblastoma."

2017 https://www.ncbi.nlm.nih.gov/pubmed/27766591
"We conclude that the combined administration of TSA and CCNU eradicates GBM cells with a higher efficacy than either drug alone, thereby opening a novel avenue for the treatment of GBM."

2015 https://www.ncbi.nlm.nih.gov/pubmed/25634603
"...these results indicate that trichostatin A (TSA) suppresses ESCC cell growth by inhibiting the activation of the PI3K/Akt and ERK1/2 pathways. TSA also promotes cell apoptosis through epigenetic regulation of the expression of apoptosis‑related protein."

2014 https://www.ncbi.nlm.nih.gov/pubmed/24464841
"Here, we investigate the effects of the HDACi trichostatin A (TSA) in U87 GBM cultures and tumorsphere-derived cells. These findings indicate that HDACis can inhibit proliferation, survival, and tumorsphere formation, and promote differentiation of U87 GBM cells, providing further evidence for the development of HDACis as potential therapeutics against GBM."

The results of clinical trials, however, did not give a good result:

Phase I/II Trial of Vorinostat Combined with Temozolomide and Radiation Therapy for Newly Diagnosed Glioblastoma: Final Results of Alliance N0874/ABTC 02.
2017 https://www.ncbi.nlm.nih.gov/pubmed/29016887

Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma.
2017 https://www.ncbi.nlm.nih.gov/pubmed/29133513

"Valproic acid has also recently been demonstrated to be a potent histone deacetylase inhibitor."
Many patients with glioblastoma take valproic acid (Depakote) against epileptic attacks. However, this has no effect on overall survival. Perhaps it is necessary to increase the dose or combination with something? I found that disulfiram increases the content of valproic acid in the blood.

And by the way, I can not find any medicine containing Trichostatin A.

Considering treatment options for high grade diffuse midline glioma H3k27m for my 8 year old daughter

Hi all,

Thanks so much to Stephen for your in depth reply to my questions about my 8 year old daughter and invitation to this blog. We moved to Norway in July and my daughter was diagnosed in early September with high grade diffuse midline glioma with H3K27m mutation after an extended biopsy, where it was determined that the tumor was not resectable. She underwent 3 further operations to have a double valve shunt put in to relieve hydrocephalus symptoms. She finished 6 weeks of radiation and Temodal about 10 days ago. The doctors want to start her on Temodal/Lomostine 4 weeks after radiation finished. If we follow this path, we could also have a full molecular analysis done and, upon recurrence, may possibly be able to access a trial using afatinib for BI1200.120, if applicable, or another targeted agent. I would also push for using repurposed drugs in the cocktail approach if possible and our conservative doctors could be convinced. 

We are trying to explore other options, and thanks to Stephen, learned about a new phase I peptide vaccine trial opening for paediatric glioma patients with mutation H3.3K27m based in San Fransisco. It is for patients who have completed 6 weeks of radiation and have not yet started chemo again, which is exactly where we are now. https://clinicaltrials.gov/ct2/show/NCT02960230

I am finding it so difficult to determine what would be the most promising, preferably least toxic option for my daughter. Any input on how promising a peptide vaccine targeted to this kind of mutation could be? Compared with temodar/lomostine/cocktail approach?

Many thanks in advance for your input.

Jeni