RESUMEN
BACKGROUND: Poor prognosis of glioblastoma patients and the extensive heterogeneity of glioblastoma at both the molecular and cellular level necessitates developing novel individualized treatment modalities via genomics-driven approaches. METHODS: This study leverages numerous pharmacogenomic and tissue databases to examine drug repositioning for glioblastoma. RNA-seq of glioblastoma tumor samples from The Cancer Genome Atlas (TCGA, n = 117) were compared to "normal" frontal lobe samples from Genotype-Tissue Expression Portal (GTEX, n = 120) to find differentially expressed genes (DEGs). Using compound gene expression data and drug activity data from the Library of Integrated Network-Based Cellular Signatures (LINCS, n = 66,512 compounds) CCLE (71 glioma cell lines), and Chemical European Molecular Biology Laboratory (ChEMBL) platforms, we employed a summarized reversal gene expression metric (sRGES) to "reverse" the resultant disease signature for GBM and its subtypes. A multiparametric strategy was employed to stratify compounds capable of blood-brain barrier penetrance with a favorable pharmacokinetic profile (CNS-MPO). RESULTS: Significant correlations were identified between sRGES and drug efficacy in GBM cell lines in both ChEMBL(r = 0.37, P < .001) and Cancer Therapeutic Response Portal (CTRP) databases (r = 0.35, P < 0.001). Our multiparametric algorithm identified two classes of drugs with highest sRGES and CNS-MPO: HDAC inhibitors (vorinostat and entinostat) and topoisomerase inhibitors suitable for drug repurposing. CONCLUSIONS: Our studies suggest that reversal of glioblastoma disease signature correlates with drug potency for various GBM subtypes. This multiparametric approach may set the foundation for an early-phase personalized -omics clinical trial for glioblastoma by effectively identifying drugs that are capable of reversing the disease signature and have favorable pharmacokinetic and safety profiles.
RESUMEN
BACKGROUND: Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, is a rare disorder marked by an increase of cerebrospinal fluid pressure that may cause severe headaches, papilledema, vision loss, and other symptoms. IIH is typically treated with shunts, but shunts are prone to malfunction and infection, resulting in many patients experiencing recurrent headaches after treatment. CASE DESCRIPTION: A 41-year-old woman with IIH presented with a history of severe headaches and seizures with documented elevated intracranial pressure (opening pressure 250 mm H2O). After failure of several medical treatments, the patient was offered surgery for symptomatic relief. Given the patient's ventricular anatomy and preference, IIH was treated with endoscopic third ventriculostomy rather than a conventional shunt. CONCLUSIONS: Reported resolution of the patient's headaches and improved quality of life following the procedure indicated that endoscopic third ventriculostomy can be used to treat IIH if ventricles are not completely slitlike. Additionally, we present a review of all previously reported cases in which endoscopic third ventriculostomy was used for the treatment of IIH.