ACTR-51. REMARKABLE RESPONSE OF A PATIENT WITH SECONDARY GBM TO A HISTONE DEACETYLASE INHIBITOR

Abstract

Abstract Glioblastomas are highly aggressive, grade IV tumors of glial cells that arise either as de novo primary tumors or as secondary tumors, which malignantly transformed from lower grade gliomas. Secondary glioblastomas have a relatively low incidence making up 5–10% of all glioblastoma diagnoses and tend to occur in younger patients. However, these tumors are still quite aggressive with survival outcomes that do not differ substantially from primary glioblastomas. Secondary glioblastomas also often harbor mutation of isocitrate dehydrogenase (IDH) enzyme, which produces the oncometabolite 2-hydroxyglutarate (2-HG) from alpha-ketoglutarate (α-KG). The accumulation of 2-HG has several downstream effects due to its competitive inhibition of α-KG-dependent enzymes, including epigenetic modification via hypermethylation of histones. Histone deacetylase inhibitors (HDACi) are a class of molecules that inhibit histone deacetylation and have been shown to have anti-tumor effect in part due to this epigenetic modification. Thus, because of their shared targets with regard to histone modification, it is plausible that HDACi could counter the oncometabolite effects of accumulated 2-HG in IDH1 mutant tumors. Since belinostat is a pan-HDACi that has improved blood-brain barrier penetration compared to many other HDACis, we conducted a pilot study that enrolled 15 patients examining its upfront use for the treatment of glioblastomas and found that it was well tolerated. One patient in particular, likely with secondary glioblastoma harboring the typical IDH1 mutation, underwent treatment with standard chemoradiation as well as belinostat on this study. For this case, a remarkable improvement in tumor burden with very significant decrease in enhancing residual tumor and restoration of magnetic resonance spectroscopy (MRS)-detectable metabolism was noted. Furthermore, improved neurocognitition and quality-of-life were also observed in this patient during the 18-month follow-up period. Collectively, these outcomes potentially support the use of belinostat as an adjuvant therapy for patients with secondary glioblastoma that harbor a mutant IDH enzyme.