Abstract LB-159: Using proton MRSI to predict response of Vorinostat treatment in recurrent GBM

Abstract

Abstract A major impediment to the development of new therapies for glioblastoma is a lack of biomarkers indicating response. The current standard for assessing tumor progression relies on changes in size of the enhancing components of the tumor on standard MRI. While this was adequate when patients were treated with radiation alone, the addition of temozolomide has significantly increased the incidence of “pseudoprogression” while use of anti-angiogenic agents (e.g. cediranib) has increased the incidence of “pseudoresponse” complicating the interpretation of standard imaging. Tissue biopsy following treatment can assess tumor viability but this is invasive and impractical. Also, many newer agents do not produce a traditional tumor “response”. Epigenetic modifications are now recognized as a frequent development in the early phases of tumorigenesis, playing a central role in tumor development. Epigenetic alterations differ significantly from genetic modifications in that they may be readily revertible by ‘‘epigenetic drugs’’ such as inhibitors of histone deacetylases (HDAC). HDACs As a promising new modality for cancer therapy the first generation of HDAC inhibitors (HDACi) are currently being tested in phase I/II clinical trials. Glioblastomas benefit from therapy with HDACi, such as vorinostat, or SAHA, demonstrating tumor redifferentiation/cytostasis rather than tumor size reduction. This limits the utility of traditional imaging methods such as MRI. Magnetic resonance spectroscopic imaging (MRSI) quantitates amino acids and other metabolic substances in tumor and normal brain, allowing characterization of metabolic processes in live tissue. Our preclinical MRSI results show that after only three days of treatment with SAHA, elevated alanine and lactate levels and reduced myo-inositol (MI), N-acetyl aspartate (NAA), and creatine levels in gliomas return toward normal brain levels. In our patient study of SAHA and temozolomide in recurrent GBMs, MRSI showed normalization (or restoration) of glioblastoma metabolism toward normal brain tissue-like metabolism following only 7 days of SAHA treatment in 50% of enrolled patients (metabolic responders). In contrast, MRSI showed no changes at day 7 in the other 50% of enrolled GBM patients (non-metabolic responders, p < 0.001). These results provide an exciting insight of the mechanisms by which HDACi exert their effect on glioblastomas. The increased biosynthetic needs of tumor cells demand a reprogramming of cellular metabolism. This creates increased energy demands and makes tumor cells more vulnerable to interventions targeting their metabolism. The mechanism by which HDACi induces redifferentiation/cytostasis in tumors may be by targeting tumor metabolism. The changes, as measured by MRSI, may serve as novel early predictors of response to HDACi-containing combination therapy in glioblastomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-159. doi:1538-7445.AM2012-LB-159