Assessing Treatment Response of Glioblastoma to an HDAC Inhibitor Using Whole-Brain Spectroscopic MRI

Abstract

Histone deacetylases regulate a wide variety of cellular functions and have been implicated in redifferentiation of various tumors. Histone deacetylase inhibitors (HDACi) are potential pharmacologic agents to improve outcomes for patients with gliomas. We assessed the therapeutic efficacy of belinostat (PXD-101), an HDACi with blood–brain barrier permeability. Belinostat was first tested in an orthotopic rat glioma model to assess in vivo tumoricidal effect. Our results showed that belinostat was effective in reducing tumor volume in the orthotopic rat glioma model in a dose-dependent manner. We also tested the antidepression activity of belinostat in 2 animal models of depression and found it to be effective. Furthermore, we confirmed that myo-inositol levels improved by belinostat treatment in vitro. In a human pilot study, it was observed that belinostat in combination with chemoradiation may delay initial recurrence of disease. Excitingly, belinostat significantly improved depressive symptoms in patients with glioblastoma compared with control subjects. Finally, spectroscopic magnetic resonance imaging of 2 patient cases from this pilot study are presented to indicate how spectroscopic magnetic resonance imaging can be used to monitor metabolite response and assess treatment effect on whole brain. This study highlights the potential of belinostat to be a synergistic therapeutic agent in the treatment of gliomas.

Final Report on Clinical Outcomes and Tumor Recurrence Patterns of a Pilot Study Assessing Efficacy of Belinostat (PXD-101) With Chemoradiation for Newly Diagnosed Glioblastoma

“…2A). 6-month PFS was 54% and 84% (p = 0.073) for the control and the belinostat cohorts, respectively, reported previously [12]. The median PFS was similar in the two groups, being 9.0 months for the control and 9.3 months for the belinostat cohorts (p = 0.75).…”

“…We previously reported interim PFS and sMRI ndings in GBM patients receiving belinostat [12,13]. With 50 months of median follow-up, we report the nal clinical outcomes and tumor recurrence patterns of patients enrolled in this study.…”

“…This suggests that development of a potent HDACi capable of penetrating the BBB has the potential to improve outcomes of patients with GBM. In addition to anti-tumor effects, we reported that belinostat restores the bottle neck enzyme levels of normal brain metabolites, N-acetylaspartate (NAA) and myo-inositol, in vitro to a greater extent than other HDACis [12]. Furthermore, spectroscopic magnetic resonance imaging (sMRI), a quantitative imaging technique that assesses metabolic responses in vivo without any contrast agent injection, has been used to show a GBM patient with an IDH mutation (without MGMT promoter hypermethylation) exhibited remarkable response to belinostat combined with standard chemoradiation therapy [13].…”

Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials

“…This strategy was used in the temozolomide phase I/II studies in patients with glioblastoma (NCT00731731) (Galanis et al, 2018) or included antimetabolites such as capecitabine in patients with non-metastatic pancreatic cancer (NCT00983268) (Chan et al, 2016). Like SAHA, other HDACis have been used: belinostat has also been combined with radiation therapy and temozolomide to treat glioblastoma (NCT02137759) (Gurbani et al, 2019); and valproic acid (HDACi) combined with capecitabine and radiotherapy in colorectal cancer where a synergistic antitumor interaction in vitro was shown (Terranova-Barberio et al, 2017a).…”

The Importance of Epigenetics in Diagnostics and Treatment of Major Depressive Disorder

“…In addition, HDACis are able to reduce the level of depressive-like behavior. In stressed mice treated with belinostat, which is also an HDACi, a significant decrease in the level of immobility was observed in the tail suspension test [ 87 , 88 , 89 ]. Another well-known HDACi, sodium butyrate (NaB), was also found to have an antidepressant effect.…”