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Author Notes:

Correspondence: H. Shim, Department of Radiology and Imaging Sciences, Winship Cancer Institute, Emory University, 1701 Uppergate Drive, C5018, Atlanta, GA 30322; Tel: 404-778-4564, Fax: 404-712-5813, Email: hshim@emory.edu

Authors' Contributions: Li Wei and Samuel Hong contributed equally to this work.

Subjects:

Research Funding:

This work was supported by NIH grants CA109366 (HS) and CA128301 (HS, JJO and XPH). This work was supported in part by the Biomedical Imaging Technology Center.

Keywords:

  • MRS
  • histone deacetylase inhibitor
  • glioma
  • SAHA
  • vorinostat
  • myo-inositol
  • orthotopic
  • depression

Early prediction of response to Vorinostat in an orthotopic glioma rat model

Tools:

Journal Title:

NMR in Biomedicine

Volume:

Volume 25, Number 9

Publisher:

, Pages 1104-1111

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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 on in treatment. Improved early predictive assessment would allow neuro-oncologists to personalize and adjust or change treatment sooner to maximize use of efficacious 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, Vorinostat, Zolinza; Merck & Co., Inc.) is an orally active, potent inhibitor of histone deacetylase (HDAC) activity. A major shortcoming of the use of HDAC inhibitors in treating brain tumor patients is the lack of reliable biomarkers to predict and determine response. Histological evaluation may reflect tumor viability following treatment but it is an invasive procedure and impractical for GBM. Another problem is that response to SAHA therapy is associated with tumor redifferentiation and cytostasis rather than tumor size reduction, thus limiting the use of traditional imaging methods. A noninvasive method to assess drug delivery and efficacy is needed. Here, we investigated whether changes in 1H MRS metabolites could render reliable biomarkers for an early response to SAHA treatment in an orthotopic animal model for glioma. Untreated tumors exhibited significantly elevated alanine and lactate levels and reduced inositol, NAA and creatine, typical changes reported in GBM compared to normal brain tissues. The proton MRS-detectable metabolites of SAHA treated tumors were restored toward those of normal-like brain tissues. In addition, reduced inositol and NAA were found to be potential biomarkers for mood alteration and depression, which may also be alleviated with SAHA treatment. Our study suggests that 1H MRS can provide reliable metabolic biomarkers at the earliest stage of SAHA treatment to predict the therapeutic response.

Copyright information:

© 2012 John Wiley & Sons, Ltd.

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