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  • Magnetic Resonance Spectroscopic Imaging Measurement of Early Response to Vorinostat Treatment in Recurrent Glioblastoma

    Final Number:
    111

    Authors:
    Jeffrey J. Olson MD; Alfredo Voloschin; Li Wei; Andrew Miller; Daniel Brat MD, PHD; Chad Holder; Hui-Kuo Shu MD, PhD; Xioaping Hu; Hyunsuk Shim

    Study Design:
    Clinical Trial

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2012 Annual Meeting

    Introduction: Early imaging detection of therapy response would abet glioblastoma (GBM) management. Epigenetic modifications are frequent early occurrences central to tumorigenesis. They differ significantly from genetic modifications in that they may be reversed by a separate class of agents, i.e., ‘‘epigenetic drugs’’ such as histone deacetylase inhibitors (HDACi). As a promising new modality for cancer therapy, the first generation of HDACi are currently being tested in phase I/II clinical trials.

    Methods: GBM alterations by HDACi, such as vorinostat (SAHA), induce tumor redifferentiation/cytostasis rather than tumor size reduction limiting the utility of traditional MRI. However, magnetic resonance spectroscopic imaging (MRSI) quantifies various metabolite levels in tumor and normal brain, and can characterize HDACi-induced chemical changes in live tissue.

    Results: In our preclinical rodent model, MRS detects metabolic response/normalization to SAHA after only 3 days of treatment: alanine and lactate reduction and elevated myo-inositol, N-acetyl aspartate and creatine. This led to our clinical study of MRSI evaluation of metabolic responses of recurrent GBMs to SAHA and temozolomide. After only 7 days of SAHA treatment, MRSI can distinguish metabolic responders from non-responders by calculation of an index of normalization/restoration of tumor metabolites towards normal brain-like metabolism. Our initial cohort (n=6) consists of 3 metabolic responders and 3 metabolic non-responders with highly significant differences in their change in metabolite levels (p < 0.001).

    Conclusions: Our results provide insight into the mechanisms by which HDACi exerts its effect on GBMs. Tumor cells are known to have altered biosynthetic needs and cellular metabolism. MRSI results suggest HDACi may induce redifferentiation in tumors by targeting tumor metabolism. Thus, MRSI measurement of metabolism is a novel modality to predict response to HDACi-containing combination therapy in GBM. More importantly, this study serves as a demonstration project for early detection of treatment effect in glioblastoma using this modality.

    Patient Care: With refinement, this technique will allow early detection of drug treatment effect on glioblatoma. Ideally this will allow early discontinuation of futile therapies or continuation of therapies destined to have a positive effect not detected by standard imaging. This is particularly important for treatments that may not cause tumor reduction, but rather stablization.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) describe the importance of epigenetic modifications in tumorigenesis, 2) understand the metabolites measurable with magnetic resonance spectroscopic imaging and, 3) ascertain the value of early detection of tumor therapy effect by vorinostat as a model for this technique.

    References:

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