SRA

In recent years, histone deacetylase inhibitors (HDACi) have garnered considerable interest for the treatment of adult and pediatric malignant brain tumors. However, owing to their broad-spectrum nature and inability to effectively penetrate the blood-brain barrier, HDACi have failed to provide significant clinical benefit to glioblastoma (GBM) patients to date. Moreover, global inhibition of HDACs results in widespread toxicity, highlighting the need for selective isoform targeting. While no isoform-specific HDACi are currently available, the second-generation hydroxamic acid-based HDACi quisinostat possesses sub-nanomolar specificity for class I HDAC isoforms, particularly HDAC1 and 2. Recently, we demonstrated that HDAC1 is the essential HDAC in GBM. Here, we panalyzed the neuro-pharmacokinetic, pharmacodynamic and radiation-sensitizing properties of quisinostat in preclinical models of GBM. We found that quisinostat is a well-tolerated and brain-penetrant molecule that significantly extended survival when administered in combination with radiation in vivo. The pharmacokinetic-pharmacodynamic-efficacy relationship was established by correlating free drug concentrations and evidence of target modulation in the brain with survival benefit. Together, these data provide a strong rationale for clinical development of quisinostat as a radiosensitizer for the treatment of GBM. Overall design: For acute treatment , mice bearing intracranial tumors were treated with either vehicle, radiation (2Gy x 3 MWF), Quisinostat (10mg/kg MWF), or combination of quisinostat + IR for one week. Three hours post last treatment, mice were sacrificed, brains harvested and processed for RNA isolation. For survival studies, mice bearing intracranial tumors were randomized into four cohorts. Cohort one was treated with vehicle (continously), cohort two with radiation (2Gy x 3; one week) alone, Quisinostat (10mg/kg MWF; continously), or combination of quisinostat (10mg/kg MWF; continously) + IR (2gy x 3; one week). Radiation was administered only for the first week when treatment was initiated. Quisinostat was administered continously on a Monday, Wednesday, Friday schedule until the animals were moribund. Mice were sacrificed and tumor samples were collected for RNA isolation once animals demonstarted neurological symptoms. RNA samples were processed for RNA-seq analysis and dIfferential gene expression analyses was performed for acute and survival conditions.