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

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.

Magnetic resonance spectroscopic imaging in the era of pseudoprogression and pseudoresponse in glioblastoma patient management

“…In this patient population, depression is consistently associated with cognitive impairment, reduced physical function, and poor quality-of-life. Our previous preclinical studies have shown that brain tumors have reduced mI and NAA compared to normal brain, confirming speculation that this may be associated with mood alterations and depression among brain tumor patients [9]. Correlations between elevated mI and NAA levels and improved mood may provide the basis for interventions in the future that improve the quality-of-life of GBM patients.…”

HDAC inhibition in glioblastoma monitored by hyperpolarized 13C MRSI

“…Mice treated with vorinostat either intravenously or intraperitoneally showed an increase in histone acetylation (acetyl‐H3 and acetyl‐H4), while proliferation of GL26 murine glioma growth was significantly inhibited . Similarly, a study in rats bearing 9L rat glioma led to a significant reduction of tumor size and a single intratumoral injection of vorinostat doubled the survival of rats bearing GL26 tumors . Based on these and other studies, vorinostat is currently in a Phase I/II clinical trial in combination with TMZ and radiation therapy in newly diagnosed GBM patients (NCT00731731)…”

Use of High-Resolution Volumetric MR Spectroscopic Imaging in Assessing Treatment Response of Glioblastoma to an HDAC Inhibitor

“…Collectively, these data suggest that myoinositol could be a biomarker to quantify response to vorinostat therapy associated with redifferentiation. A preclinical study [42] showed that normalization or restoration of 1 H MRS metabolites could be reliable imaging biomarkers for an early favorable response to vorinostat treatment in an orthotopic animal model for glioma and that reduction in myoinositol and NAA was found to be a potential biomarker for depression, which may also be alleviated with vorinostat treatment.…”