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Page 10 of 18 Yelton et al. Neuroimmunol Neuroinflammation 2018;5:46 I http://dx.doi.org/10.20517/2347-8659.2018.58

p21Waf1/Cip1 and the pro-apoptotic protein Bad and the decreased expression of the anti-apoptotic proteins
[73]
Bcl-xL and Bcl-2) . Finally, of the two miscellaneous HDAC inhibitors, DATS has been shown to cause
upregulation of the cell cycle inhibitor p21Waf1/Cip1 and the tumor suppressor p53 in order to cause cell
cycle arrest in glioblastoma cells and is unique in that it is derived from garlic and demonstrates less toxicity
[74]
to normal cells than other HDAC inhibitors . Tubacin, the other miscellaneous HDAC inhibitor, is a
[75]
specific for HDAC6 and it has been proposed to be useful because HDAC6 is known to be increased in
certain high-grade gliomas. All the above HDAC inhibitors have shown considerable promise for growth
inhibition in glioblastoma, but only a few of these agents have made it into the clinical trials as of now.

Only a few selected HDAC inhibitors that have shown promise in the pre-clinical realm translate so
seamlessly over to show efficacy in the clinical realm. Vorinostat, romidepsin, and valproic acid are
particularly notable to have seen translational promise in the preclinical realm as well as in the clinical
realm. Vorinostat as a monotherapy progressed through multiple Phase I and Phase II trials, with the
results of one Phase II trial indicating that it was well tolerated in recurrent glioblastoma patients,
and its efficacy was seen to extend life by a few months in a subpopulation of those with recurrent
[76]
glioblastoma . Romidepsin also went through both Phase I and Phase II trials but had disappointing
outcomes in progression free survival with the conclusion that although the drug demonstrated success
in the preclinical arena, when used in clinics an inadequate amount of the drug reached the actual tumor
[77]
in the CNS . However, this agent showed success when used in combination therapies. Valproic acid
similarly showed success in clinical trials, but only when used in combination therapies and not when
[78]
used as a monotherapy . In fact, many other HDAC inhibitors listed in Table 2 in various trials for use in
glioblastoma are in combination therapies and may yet show results when combined with the standard-of-
care agents. However, HDAC inhibitors when used as monotherapy have yet to yield the progression free
survival results that the preclinical mechanistic evidence would suggest, with an exception to vorinostat (and
even then, only modestly so). To understand the full picture of these promising new agents, one must look at
both the preclinical and the clinical data housed in trials. Unfortunately, there seems to be a wealth of new
mechanisms to be revealed and understood as to the biological pathways these agents are inhibiting. A more
profound understanding of glioblastoma pathogenesis and the associated aberrant pathways inhibited by
these agents is essential to translate the benefits from the preclinical bench to the clinical arena.

HDAC INHIBITORS FOR ENHANCING ANTITUMOR IMMUNITY IN GLIOBLASTOMA
While there have been a variety of preclinical studies regarding the effects of HDAC inhibitors specifically in
glioblastoma, one of the most interesting effects is alteration of the tumor itself to increase tumor susceptibility
to antitumor immune attack. Many cells of the immune system act as surveillance cells, effectively patrolling
[79]
the body to eliminate neoplastic cells as soon as they are found . However, many tumors are notorious for
down regulating these markers on their surfaces, effectively “hiding” from the immune system to evade
elimination and continue their unfettered growth. While there are many important cell types (microglia, T
cells, etc.) involved in the surveillance of the body’s somatic tissues for signs of pathological changes, one of
the cell types most important to the preclinical mechanism of HDAC inhibitors and antitumor immunity
are NK cells. These cells act to “check” or surveille surface proteins displayed on the exterior of many cells,
checking these cells for signs of stress, infection, or neoplastic change. If an NK cell finds a cell within the
body that has undergone one of these pathological changes, the NK cell releases cytotoxic granules containing
toxic compounds known as perforins and granzymes, which act synergistically to induce apoptosis in the
target cell. These NK cells have been described in the literature to be the agents that lyse GBM cells as they are
recognized during their surveillance, with HDAC inhibitors playing a role in upregulating the surface markers
that help to mark these malignant cells as a target for elimination [19,22] .

The NK cells possess a constitutively expressed receptor on their surface known as natural killer group 2D
[80]
(NKG2D) that is essential for recognition of abnormal human tissues . This receptor recognizes a ligand