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Controlled Clinical Trial
. 2019 Mar;5(1):53-60.
doi: 10.18383/j.tom.2018.00031.

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

Saumya S Gurbani  1   2 , Younghyoun Yoon  1 , Brent D Weinberg  3 , Eric Salgado  1 , Robert H Press  1 , J Scott Cordova  1 , Karthik K Ramesh  1   2 , Zhongxing Liang  1 , Jose Velazquez Vega  4 , Alfredo Voloschin  5 , Jeffrey J Olson  6 , Eduard Schreibmann  1 , Hyunsuk Shim  1   2   3 , Hui-Kuo G Shu  1
Affiliations
Controlled Clinical Trial

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

Saumya S Gurbani et al. Tomography. 2019 Mar.

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.

Keywords: belinostat; glioblastoma; histone deacetylase inhibitor; orthotopic rat glioma model; spectroscopic MRI.

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Figures

Figure 1.
Figure 1.
One-year timeline of chemotherapy, intravenous belinostat, radiation, spectroscopic magnetic resonance imaging (sMRI) scanning, Inventory of Depressive Symptomatology Self Report (IDS-SR) survey, and neurocognitive testing for patients in NCT02137759. Hashed boxes indicate items conducted for patients in only the treatment arm of the study.
Figure 2.
Figure 2.
A rat model of stereotactically injected 9L glioma cells shows a dose-dependent response in both tumor volume and mood/activity levels when treated with belinostat.
Figure 3.
Figure 3.
Two mouse models of depression to assess antidepressive effect of belinostat: Force-swim test measuring the time spent in immobility during 2–8 minutes (6 minutes) (A). Tail suspension test measuring the time spent in immobility in mice treated with lipopolysaccharide (LPS) for 6 minutes. Five mice were used in each group (B).
Figure 4.
Figure 4.
Progression-free survival (PFS) of patients in both arms of the study up to 1 year (A). Age indicates age at time of surgery, and PFS is right-censored from the time of surgery. Kaplan–Meier curves for the 2 arms of the study; tick marks indicate time of censoring (B).
Figure 5.
Figure 5.
Longitudinal imaging of a patient in the control arm of the study. An sMRI map of choline indicates a response to chemoradiation between baseline and the first follow-up; however, standard clinical imaging indicates potential progression of disease. Further follow-up indicates that the imaging findings at 1 month were attributable to pseudoprogression.
Figure 6.
Figure 6.
Longitudinal imaging of a patient in the belinostat (treatment) arm of the study. An sMRI map of choline indicates a response to chemoradiation as assessed at 1 month post-RT. Additional follow-up imaging indicates the pseudoprogression phenomenon occurring at 3 month post-RT, resolving by 4 month post-RT.
See this image and copyright information in PMC

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