Glioblastoma (GBM) is the most common primary brain tumor and is uniformly fatal despite aggressive surgical and adjuvant therapy. Since survival is short, it is critical to determine the value of therapy early during treatment. Improved early predictive assessment would allow neuro-oncologists to adjust or change treatment sooner to maximize use of the most effective therapy. During carcinogenesis, tumor suppressor genes can be silenced by aberrant histone deacetylation. This epigenetic modification has become an important target for tumor therapy. Suberoylanilide hydroxamic acid (SAHA) is an orally active, potent inhibitor of histone deacetylase (HDAC) activity. Clinical effects may include tumor control and cerebral biochemical alterations that may improve mood, correcting the depressive symptoms experienced by many of these patients. Clinical evaluation of SAHA in recurrent GBM is currently ongoing within the NCI-funded Adult Brain Tumor Consortium (ABTC) because of the promising preclinical results in malignant gliomas. In addition, a phase I evaluation in newly diagnosed GBM in combination with temozolomide and radiation therapy has just been opened by this group. The lack of reliable biomarkers to predict early response severely hampers the treatment of GBM tumor patients with HDAC inhibitors. Frequent histological evaluation is impractical for GBM due to the risks of invasive biopsies and unreliable endpoints. Another problem is that response to SAHA therapy is associated with tumor redifferentiation/cytostasis rather than tumor size reduction, limiting the use of traditional imaging methods. We propose to fill this void by optimizing an MRS method to pharmacodynamically assess biomarkers noninvasively and longitudinally. In this manner, we evaluate the efficacy of drug delivery and therapeutic effect early in the course of the treatment. Here our objective is to develop an MRS-based tool to aid clinicians in the early determination of the value of SAHA when administered to recurrent GBM patients treated with SAHA in combination with temozolomide, thereby identifying patients most likely to benefit. In addition, we will determine whether reduced inositol and NAA are reliable biomarkers of altered mood or depression in GBM patients, which may alleviated with SAHA treatment. Therefore, we plan to assess for potential improvement in the mood of recurrent GBM patients by correlating MRS data with a psychiatric evaluation. Establishing reliable MRS biomarkers to assess early response would clearly be of value in personalizing the management of glioblastoma patients by allowing clinicians to adjust the dose of SAHA treatment or seek alternative treatment. The ability to do this would be a highly innovative use of established technology (MRS) that would be readily implemented at most institutions. Importantly, our MRS-based tool will assess the restoration of normal brain metabolism, and indirectly monitor the subject's quality of life.

Public Health Relevance

During carcinogenesis, tumor-suppressor genes can be silenced by aberrant histone deacetylation. This epigenetic modification has become an important target for tumor therapy. Vorinostat (SAHA, Zolinza;Merck &Co., Inc., Whitehouse Station, NJ) is an orally active, potent inhibitor of aberrant histone deacetylation activity that is currently being evaluated in glioblastoma patients. In this study, we will establish an important clinical tool to predict therapeutic response soon after treatment initiation. Our MRS- based tool will aid clinicians in early modification of SAHA treatment or in seeking alternative treatments in those with glioblastoma.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-SBIB-V (51))
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Tandon, Pushpa
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Emory University
Schools of Medicine
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Wei, Li; Hong, Samuel; Yoon, Younghyoun et al. (2012) Early prediction of response to Vorinostat in an orthotopic rat glioma model. NMR Biomed 25:1104-11