Project description: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.
Project description:Glioblastoma (GBM) is a common and aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of a tetracyclic dicarboximide (referred to as MM0299) identified in a screen for compounds with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a “shunt” pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to block the growth of mouse and human glioma stem-like cells by depleting cellular cholesterol. In comparison to a known LSS inhibitor, MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. Critical for its application in the brain, we report an MM0299 derivative that is orally bioavailable, brain-penetrant and induces the production of EPC in orthotopic GBM tumors but not normal mouse brain. These studies have implications for the development of an LSS inhibitor to treat GBM or other neurologic indications.
Project description:This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled brain metastasis. The study will have three phases, Phase 1, Phase 2a and Phase 2b.
Project description:The expression profiling of a total of 2085 microRNAs in 5 glioblastoma and 5 normal brain cases, which had been consecutively operated on within a defined short period of time
Project description:MicroRNAs (miRNAs) are small (21-25 nucleotide in length) non-coding RNA molecules that negatively regulate protein expression. They are linked to cancer development and maintenance. In this work, studying gene expression profiles of 340 mammalian miRNAs with DNA microarrays, we selected 10 miRNAs gene features able to distinguish primary from secondary glioblastoma type; furthermore we verified that miR-21 and miR-155 up-regulatation seems to characterize the glioblastoma tumour state since it was found up-regulated in all samples analyzed compared to adult brain noneoplastic tissue. Since miR-21 function in glioblastoma cells was addressed previously we concentrated our efforts on miR-155 function. We found that miR-155 levels were markedly elevated both in primary and secondary glioblastomas tumours, in glioblastoma cell cultures and in 4 glioblastoma cell lines (U87, A172, LN229, and LN308) compared with adult brain tissue, CHP212-neuroblastoma cell lines and DAOY-1-medulloblastoma cell line. Since one of the miR-155 target was gamma-aminobutyric acid (GABA) A receptor (GABRA1) we verified if there was a relation between miR-155 up-regulation and GABRA1 expression. We demonstrated that, in cultured glioblastoma cells, knockdown of miR-155, which lower miR-155 expression to normal level, restore the normal expression of the gamma-aminobutyric acid (GABA) A receptor (GABRA1), making glioblastoma cells responsive to GABA cell cycle inhibiting signals. Our data suggest that aberrantly over-expressed miR-155 contribute to the malignant phenotype of the glioblastoma cells, promoting their unlimited growth. Keywords: miRNA expression profile We studied the expression profiles of 340 miRNAs in 97 glioblastoma tissues, of which 66 were primary glioblastomas and 27 were secondary glioblastomas. We have 66 replicates of primary glioblastoma and 27 replicates of secondary glioblastoma, each hybridized with the respective adult non-neoplastic brain tissue as a control.
Project description:MicroRNAs (miRNAs) are small (21-25 nucleotide in length) non-coding RNA molecules that negatively regulate protein expression. They are linked to cancer development and maintenance. In this work, studying gene expression profiles of 340 mammalian miRNAs with DNA microarrays, we selected 10 miRNAs gene features able to distinguish primary from secondary glioblastoma type; furthermore we verified that miR-21 and miR-155 up-regulatation seems to characterize the glioblastoma tumour state since it was found up-regulated in all samples analyzed compared to adult brain noneoplastic tissue. Since miR-21 function in glioblastoma cells was addressed previously we concentrated our efforts on miR-155 function. We found that miR-155 levels were markedly elevated both in primary and secondary glioblastomas tumours, in glioblastoma cell cultures and in 4 glioblastoma cell lines (U87, A172, LN229, and LN308) compared with adult brain tissue, CHP212-neuroblastoma cell lines and DAOY-1-medulloblastoma cell line. Since one of the miR-155 target was gamma-aminobutyric acid (GABA) A receptor (GABRA1) we verified if there was a relation between miR-155 up-regulation and GABRA1 expression. We demonstrated that, in cultured glioblastoma cells, knockdown of miR-155, which lower miR-155 expression to normal level, restore the normal expression of the gamma-aminobutyric acid (GABA) A receptor (GABRA1), making glioblastoma cells responsive to GABA cell cycle inhibiting signals. Our data suggest that aberrantly over-expressed miR-155 contribute to the malignant phenotype of the glioblastoma cells, promoting their unlimited growth. Keywords: miRNA expression profile
Project description:Tumor-initiating cells (TICs) play a critical role in glioblastoma (GBM) maintenance being responsible for its heterogeneity and resistance to standard therapy. A step toward clinical translation includes GBM TIC targeting. Among the molecules tested for GBM treatment, are those targeting epigenetic modifiers. By using patient-derived TICs and xenograft orthotopic models, we identified Lysine-specific histone demethylase 1A (LSD1) as a potentially druggable target in GBM. LSD1-directed therapy by means of the selective, orally bioavailable and brain penetrant inhibitor DDP_38003 effectively impairs growth, stem-like features and tumorigenic potential of GBM TICs. Our findings point to LSD1 as a positive regulator of Activating Transcription Factor 4 (ATF4)-dependent response in all stress conditions arising during tumor growth and therapy. Thus, through the downregulation of either ATF4 and its adaptive genes, LSD1 targeting is likely a promising strategy to hit GBM TICs by counteracting the ATF4-mediated adaptation to stress.
Project description:We used microarrays to investigate the whole genome gene expression level changes of LncRNAs in human Glioblastoma multiforme (GBM) and normal brain tissues, and try to find out some LncRNA associated with the tumorigenesis of GBM.