A5006525866- Glioma Diagnosis and Treatment
- Immune cells in cancer
- Epigenetics and DNA Methylation
- PARP inhibition in cancer therapy
- Neuroinflammation and Neurodegeneration Mechanisms
- interferon and immune responses
- Immunotherapy and Immune Responses
- Adenosine and Purinergic Signaling
- Chemokine receptors and signaling
- Cancer Genomics and Diagnostics
- Nanoplatforms for cancer theranostics
- Autophagy in Disease and Therapy
- Histone Deacetylase Inhibitors Research
- MicroRNA in disease regulation
- Virus-based gene therapy research
- Cancer Research and Treatments
- Peptidase Inhibition and Analysis
- Cancer, Hypoxia, and Metabolism
- Immune Cell Function and Interaction
- Neuroblastoma Research and Treatments
University of Michigan
2020-2024
Ann Arbor Center for Independent Living
2024
Regional West Medical Center
2020
Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C receptor-4 (CXCL12/CXCR4) signaling pathway activated in associated progression. Although CXCR4 antagonist (AMD3100) has been proposed as attractive anti-GBM target, it...
Mutant isocitrate dehydrogenase 1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into 2 molecular subgroups: 1p/19q codeletion/TERT-promoter mutations or inactivating in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work focuses on glioma subtypes harboring mIDH1, TP53, ATRX inactivation. IDH1-R132H gain-of-function mutation that converts α-ketoglutarate 2-hydroxyglutarate (D-2HG). The role D-2HG within the tumor...
Mutant isocitrate-dehydrogenase 1 ( mIDH1 ) synthesizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of glioma cells’ transcriptome by inhibiting DNA and histone demethylases. We show that efficacy immune-stimulatory gene therapy (TK/Flt3L) is enhanced in gliomas, due to myeloid compartment infiltrating tumor microenvironment (TME). uncovered immature cells TME are mainly nonsuppressive neutrophils preneutrophils. Myeloid cell was triggered granulocyte...
Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children USA. Sixteen percent hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy therapeutic resistance pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation led to downregulation DNA repair pathways....
Gliomas are the most common primary brain tumors. High-Grade have a median survival (MS) of 18 months, while Low-Grade (LGGs) an MS approximately 7.3 years. Seventy-six percent patients with LGG express mutated isocitrate dehydrogenase (mIDH) enzyme. Survival these ranges from 1 to 15 years, and tumor mutational burden 0.28 3.85 somatic mutations/megabase per tumor. We tested hypothesis that would predict tumors bearing mIDH.We analyzed effect on patients' using clinical genomic data 1199...
Mutant isocitrate dehydrogenase 1 (mIDH1; IDH1 R132H ) exhibits a gain of function mutation enabling 2-hydroxyglutarate (2HG) production. 2HG inhibits DNA and histone demethylases, inducing epigenetic reprogramming corresponding changes to the transcriptome. We previously demonstrated 2HG-mediated enhances DNA-damage response confers radioresistance in mIDH1 gliomas harboring p53 ATRX loss mutations. In this study, RNA-seq ChIP-seq data revealed human mouse glioma neurospheres have...
Numerous therapies aimed at driving an effective anti-glioma response have been employed over the last decade; nevertheless, survival outcomes for patients remain dismal. This may be due to expression of immune-checkpoint ligands such as PD-L1 by glioblastoma (GBM) cells which interact with their respective receptors on tumor-infiltrating effector T curtailing activation anti-GBM CD8
ABSTRACT Diffuse hemispheric glioma (DHG), H3 G34-mutant, representing 9-15% of cases, are aggressive Central Nervous System (CNS) tumors with poor prognosis. This study examines the role epigenetic reprogramming immune microenvironment and response to immune-mediated therapies in G34-mutant DHG. To this end, we utilized human DHG biopsies, primary cultures, genetically engineered mouse models (GEMMs). Our findings show that G34 mutation alters histone marks’ deposition at promoter enhancer...
Abstract Gliomas are primary brain tumors with a poor prognosis. IDH1R132H exhibits gain of function mutation leading to 2-hydroxyglutarate (2HG) production. We previously demonstrated, 2-HG mediated epigenetic rewiring is associated better prognosis and its presence impacts several cellular functions including immune responses enhanced DNA-damage response in gliomas harboring p53 ATRX loss-of-function mutations. Also, elicits metabolic reprogramming which implies that could modify the...
ABSTRACT Mutation in isocitrate dehydrogenase ( mIDH ) is a gain of function mutation resulting the production oncometabolite, R-2-hydroxyglutarate, that inhibits DNA and histone demethylases. The resultant hypermethylation phenotype reprograms glioma cells’ transcriptome elicits profound effects on immunity. We report mouse models human gliomas, mIDH1 context ATRX TP53 inactivation results global expansion granulocytic myeloid compartment. Single-cell RNA-sequencing coupled with mass...
Abstract Glioblastoma multiforme (GBM) is an aggressive primary brain tumor, with poor prognosis. Major obstacles hampering effective therapeutic response in GBM are tumor heterogeneity, high infiltration of immunosuppressive myeloid cells, and the presence blood-brain barrier. The C-X-C Motif Chemokine Ligand 12/ Receptor 4 (CXCL12/ CXCR4) signaling pathway implicated invasion cell cycle progression. While CXCR4 antagonists (AMD3100) has a potential anti-GBM effects, its pharmacokinetic...
ABSTRACT Gliomas are the most common primary brain tumors. High Grade have a median survival of 18 months, while Low (LGG) ∼7.3 years. Seventy-six percent patients with LGG express mutated isocitrate dehydrogenase (mIDH1) enzyme (IDH1 R132H ). Survival these ranges from 1-15 years, and tumor mutational burden 8 to 447 total somatic mutations per tumor. We tested hypothesis that would predict tumors bearing mIDH1 . analyzed effect on patients’ using clinical genomic data 1199 glioma The...
Abstract Mutation in isocitrate dehydrogenase (mIDH) is the main genetic lesion that defines clinical glioma subtypes and prognosis. This gain of function mutation associated with production oncometabolite, R-2-hydroxyglutarate, inhibits α-ketoglutarate dependent enzymes such as TET2 Jumonji-C domain containing demethylases. The resultant epigenetic modifications elicit profound effects on tumor biology glioma-infiltrating immune cells. Here, we report genetically engineered mouse models(1),...