Project description:Metabolic gene expression analysis to explore ICG-001’s impact on metabolic changes associated with glioma differentiation after disrupting the CBP/β-Catenin interaction by treating patient-derived GBM cell lines PBT147 and PBT030 with ICG-001 (0, 5, or 10 µM) for 24 and 72 h using Nanostring nCounter platform
Project description:Metabolic gene expression analysis to explore ICG-001’s impact on metabolic changes associated with glioma differentiation after disrupting the CBP/β-Catenin interaction by treating patient-derived GBM cell lines PBT147 and PBT030 with ICG-001 (0, 5, or 10 µM) for 24 and 72 h using Nanostring nCounter platform
Project description:Analysis of the effects of targeting NOS2 at the gene expression level. Our studies demonstrated a role for NOS2 in glioma biology through the maintenance of the glioma stem cell phenotype. Microarray results provide novel targets of NOS2 and suggest mechanisms through which NOS2 contributes to glioma stem cell biology. Glioma stem cells isolated from two different human glioma xenografts were infected with a non-targeting control shRNA or two different shRNAs directed against NOS2 (each treatment in each tumor performed in technical duplicates).
Project description:Immune checkpoint blockade (ICB) therapy is effective against many cancers, though resistance remains a major issue and novel strategies are needed to improve clinical outcomes. We studied ICB response in a cohort of patients with ovarian clear cell carcinoma (OCCC), a cancer type that poses significant clinical challenges and lacks effective therapies. Here we observed significantly prolonged overall and progression-free survival in patients with tumors harboring PPP2R1A inactivating mutations (PPP2R1Amut). Importantly, findings were validated in additional ICB-treated patient cohorts across multiple cancer types. Translational analyses from tumor biopsies demonstrated enhanced interferon-gamma signaling, and presence of tertiary lymphoid structures at baseline, as well as enhanced immune infiltration and expansion of CD45RO+ CD8+ T cells in the tumor neighborhood upon ICB treatment, in PPP2R1Amut tumors. Parallel pre-clinical investigations showed that targeting PPP2R1A (via pharmacologic inhibition or knockdown) in in vitro and in vivo models was associated with improved survival in the setting of treatment with several forms of immunotherapy, including chimeric antigen receptor-T cell therapy and ICB. Results from these studies suggest that therapeutic targeting of PPP2R1A may represent an effective strategy to improve patient outcomes following ICB or other forms of immunotherapy, though additional mechanistic and therapeutic insights are needed.
Project description:Analysis of the effects of targeting NOS2 at the gene expression level. Our studies demonstrated a role for NOS2 in glioma biology through the maintenance of the glioma stem cell phenotype. Microarray results provide novel targets of NOS2 and suggest mechanisms through which NOS2 contributes to glioma stem cell biology.
Project description:Primary mismatch-repair deficient (priMMRD) gliomas are lethal tumours characterized by hypermutation, resistance to chemoradiation, and variable response to immunotherapy.To investigate the mechanisms governing the emergence of driver mutations and their impact on gliomagenesis and outcome, we analyzed genomic and clinical data of 162 priMMRD gliomas. We identified three subgroups defined by secondary driver mutations in replicative DNA polymerases or IDH1. These subgroups converge on glioma drivers through distinct combinations of genomic instability-generating mechanisms, displaying an inverse correlation between point mutation and copy number alteration. MMRD signaturesdrive the emergence of specific mutations in TP53 and IDH1, notably excluding common pediatric glioma drivers. Global hypomethylation stratifies priMMRD gliomas into a unique methylation cluster. DNA-polymerasemut priMMRD gliomas exhibit ultrahypermutation, an immune-hot microenvironment, and immunotherapy responsiveness, whereas IDH1mut priMMRD gliomas are immune-cold and immunotherapy resistant. MMRD-driven gliomagenesis defines the role of non-random mutagenesis-patterns in cancer development, providing frameworks for targeted and immune-therapeutics.