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

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, ie, “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). CONCLUSION: 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.