Grand rounds at the National Institutes of Health: HDAC inhibitors as radiation modifiers, from bench to clinic - PubMed (original) (raw)

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Grand rounds at the National Institutes of Health: HDAC inhibitors as radiation modifiers, from bench to clinic

Jacob E Shabason et al. J Cell Mol Med. 2011 Dec.

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumour. Patients afflicted with this disease unfortunately have a very poor prognosis, and fewer than 5% of patients survive for 5 years from the time of diagnosis. Therefore, improved therapies to treat this disease are sorely needed. One such class of drugs that have generated great enthusiasm for the treatment of numerous malignancies, including GBM, is histone deacetylase (HDAC) inhibitors. Pre-clinical data have demonstrated the efficacy of various HDAC inhibitors as anticancer agents, with the greatest effects shown when HDAC inhibitors are used in combination with other therapies. As a result of encouraging pre-clinical data, numerous HDAC inhibitors are under investigation in clinical trials, either as monotherapies or in conjunction with other treatments such as chemotherapy, biologic therapy or radiation therapy. In fact, two actively studied HDAC inhibitors, vorinostat and depsipeptide, were recently approved for the treatment of refractory cutaneous T cell lymphoma. In this review, we first present a patient with GBM, and then discuss the pathogenesis, epidemiology and current treatment options of GBM. Finally, we examine the translation of pre-clinical studies that have demonstrated HDAC inhibitors as potent radiosensitizers in in vitro and in vivo models, to a phase II clinical trial combining the HDAC inhibitor, valproic acid, along with temozolomide and radiation therapy for the treatment of GBM.

Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd No claim to US government works.

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Figures

Fig 1

Fig 1

(A) T1 and T2 representative MRI images of the patient at diagnosis. These images display a ring-enhancing lesion in the left parietal occipital lobe, characteristic of GBM. (B) Representative pathological image of GBM displaying pseudopalisading formation of malignant cells surrounding areas of necrosis (Frontalcortex.com).

Fig 2

Fig 2

Excerpt graphs from Camphausen et al. showing in vitro and in vivo radiosensitization of glioma cells by valproic acid treatment (28). (A) U251 and SF539 glioma cells were treated with valproic acid both before and following radiation. Clonogenic survival curves reveal an increase in radiosensitivity in valproic acid treated cells. (B) The effects of valproic acid and radiation on tumour growth delay. U251 glioma cells were implanted into the hind leg of mice and divided into four treatment groups: (1) control, (2) 4 Gy radiation, (3) valproic acid, (4) valproic acid and 4 Gy radiation. The combination treatment regimen showed the most significant tumour growth delay.

Fig 2

Fig 2

Excerpt graphs from Camphausen et al. showing in vitro and in vivo radiosensitization of glioma cells by valproic acid treatment (28). (A) U251 and SF539 glioma cells were treated with valproic acid both before and following radiation. Clonogenic survival curves reveal an increase in radiosensitivity in valproic acid treated cells. (B) The effects of valproic acid and radiation on tumour growth delay. U251 glioma cells were implanted into the hind leg of mice and divided into four treatment groups: (1) control, (2) 4 Gy radiation, (3) valproic acid, (4) valproic acid and 4 Gy radiation. The combination treatment regimen showed the most significant tumour growth delay.

Fig 3

Fig 3

A series of T1 and T2 weighted Brain MRIs from the presented patient with GBM. (A) Represents images from the initial diagnosis. (B) Represents images shortly after gross surgical resection, showing typical post-surgical changes. (C) Represents the most recent MRI images with no evidence of disease recurrence 3 years after the initial diagnosis of GBM.

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