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.

PARP Inhibitors - Combining SAHA and Olaparib? Preparing for plan b

Hi All,

My Dad was diagnosed with a GBM in October 2016 and has since had chemoradiation, on his 5th TMZ cycle, and has had two Avastin infusions.

The Avastin infusions immediately cleared up his MRIs (the inflammation, not the tumor) and have allowed us to taper his decadron from 4mg/day to 2.5mg/day, but we know that Avastin is not the long term answer so I am preparing for our next step.

As I'm sure everyone is, I'm pushing to have a better than standard of care "newly diagnosed stage" plan (which is right now), as well as a plan for if/when we hit the "recurrent stage".

My last post mentioned our NO's interest in Abemaciclib and the possibility of getting compassionate use, but since then our NO was at a Brain Tumor Conference in Zurich, Switzerland (Lilly, the drug manufacturer of Abemaciclib was there) and did not receive any promising results or information to keep us pursuing this path.

Our next plan is to look at PARP Inhibitors. An article and strategy that quickly caught my families attention is about the combination of SAHA (an HDAC class I + II inhibitor) and Olaparib (a PARP inhibitor).

See the following article below:
https://www.ncbi.nlm.nih.gov/pubmed/26794465

and for full article see this link:
http://onlinelibrary.wiley.com/doi/10.1016/j.molonc.2015.12.014/full

A previous post on this blog mentioned Rucaparib (another PARP inhibitor) has been shown to not penetrate the blood brain barrier effectively, but has anyone heard specific results about oliparib?

Both Olaparib and SAHA are being tested individually in currently active clinical trials with TMZ but I have not been able to find any of the results.

One caution our NO mentioned was that PARP inhibitors can cause issues with blood counts, especially for someone who is on TMZ cycles.

Would love to hear what you all think about this plan and whether you have heard the good/bad/ugly on the PARP Inhibitor trials I mentioned about.

Amazing community we have here. Thank you all for the time.

Ari
Oakland, CA