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

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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.

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The Inventory of Depressive Symptomatology (IDS): psychometric properties.

A Rush, C Gullion, M. Basco … (1996)

The psychometric properties of the 28- and 30-item versions of the Inventory of Depressive Symptomatology, Clinician-Rated (IDS-C) and Self-Report (IDS-SR) are reported in a total of 434 (28-item) and 337 (30-item) adult out-patients with current major depressive disorder and 118 adult euthymic subjects (15 remitted depressed and 103 normal controls). Cronbach's alpha ranged from 0.92 to 0.94 for the total sample and from 0.76 to 0.82 for those with current depression. Item total correlations, as well as several tests of concurrent and discriminant validity are reported. Factor analysis revealed three dimensions (cognitive/mood, anxiety/arousal and vegetative) for each scale. Analysis of sensitivity to change in symptom severity in an open-label trial of fluoxetine (N = 58) showed that the IDS-C and IDS-SR were highly related to the 17-item Hamilton Rating Scale for Depression. Given the more complete item coverage, satisfactory psychometric properties, and high correlations with the above standard ratings, the 30-item IDS-C and IDS-SR can be used to evaluate depressive symptom severity. The availability of similar item content for clinician-rated and self-reported versions allows more direct evaluations of these two perspectives.

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The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice.

John F. Cryan, Cedric Mombereau, Annick Vassout (2005)

Since its introduction almost 20 years ago, the tail suspension test has become one of the most widely used models for assessing antidepressant-like activity in mice. The test is based on the fact that animals subjected to the short-term, inescapable stress of being suspended by their tail, will develop an immobile posture. Various antidepressant medications reverse the immobility and promote the occurrence of escape-related behaviour. This review focuses on the utility this test as part of a research program aimed at understanding the mechanism of action of antidepressants. We discuss the inherent difficulties in modeling depression in rodents. We describe how the tail suspension differs from the closely related forced swim test. Further, we address some key issues associated with using the TST as a model of antidepressant action. We discuss issues regarding whether it satisfies criteria to be a valid model for assessing depression-related behavioural traits. We elaborate on the tests' ease of use, strain differences observed in the test and gender effects in the test. We focus on the utility of the test for genetic analysis. Furthermore, we discuss the concept of whether immobility maybe a behavioural trait relevant to depression. All of the available pharmacological data using the test in genetically modified mice is collated. Special attention is given to selective breeding programs such as the Rouen 'depressed' mice which have been bred for high and low immobility in the tail suspension test. We provide an extensive pooling of the pharmacological studies published to date using the test. Finally, we provide novel pharmacological validation of an automated system (Bioseb) for assessing immobility. Taken together, we conclude that the tail suspension test is a useful test for assessing the behavioural effects of antidepressant compounds and other pharmacological and genetic manipulations relevant to depression.

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Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents

Madhusoodanan Mottamal, Shilong Zheng, Tien Huang … (2015)

Histone dacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones and regulate expression of tumor suppressor genes. They are implicated in many human diseases, especially cancer, making them a promising therapeutic target for treatment of the latter by developing a wide variety of inhibitors. HDAC inhibitors interfere with HDAC activity and regulate biological events, such as cell cycle, differentiation and apoptosis in cancer cells. As a result, HDAC inhibitor-based therapies have gained much attention for cancer treatment. To date, the FDA has approved three HDAC inhibitors for cutaneous/peripheral T-cell lymphoma and many more HDAC inhibitors are in different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. In the intensifying efforts to discover new, hopefully more therapeutically efficacious HDAC inhibitors, molecular modeling-based rational drug design has played an important role in identifying potential inhibitors that vary in molecular structures and properties. In this review, we summarize four major structural classes of HDAC inhibitors that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.

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Author and article information

Journal

Journal ID (nlm-ta): Tomography

Journal ID (iso-abbrev): Tomography

Journal ID (publisher-id): TOMOG

Title: Tomography

Publisher: Grapho Publications, LLC (Ann Abor, Michigan )

ISSN (Print): 2379-1381

ISSN (Electronic): 2379-139X

Publication date (Print): March 2019

Volume: 5

Issue: 1

Pages: 53-60

Affiliations

[1 ]Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA;

[2 ]Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA;

Departments of [3 ]Radiology and Imaging Sciences,

[4 ]Pathology and Laboratory Medicine;

[5 ]Hematology and Medical Oncology, and

[6 ]Neurosurgery, Emory University School of Medicine, Atlanta, GA

Author notes

Corresponding Authors: Hyunsuk Shim, PhD Department of Radiation Oncology, Winship Cancer Institute of Emory University, 1701 Uppergate Drive, Atlanta, GA 30322; E-mail: hshim@ 123456emory.edu ; and Hui-Kuo Shu, E-mail: hshu@ 123456emory.edu

Article

Publisher ID: TOMO-2018-00031

DOI: 10.18383/j.tom.2018.00031

PMC ID: 6403031

PubMed ID: 30854442

SO-VID: 3723207d-810d-46cc-8eea-cfc1d346d6c3

License:

This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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

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Abstract

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Genome Engineering using CRISPR

Most cited references 17

The Inventory of Depressive Symptomatology (IDS): psychometric properties.

The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice.

Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents

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