A5009886555- Glioma Diagnosis and Treatment
- Neuroblastoma Research and Treatments
- Cancer-related molecular mechanisms research
- MicroRNA in disease regulation
- Cell Adhesion Molecules Research
- FOXO transcription factor regulation
- Chromatin Remodeling and Cancer
- Brain Metastases and Treatment
- RNA Research and Splicing
- Renal and related cancers
- Caveolin-1 and cellular processes
- Protein Degradation and Inhibitors
- Gestational Trophoblastic Disease Studies
- Pluripotent Stem Cells Research
- Cardiovascular Function and Risk Factors
- Genetics and Neurodevelopmental Disorders
- Renal cell carcinoma treatment
- Receptor Mechanisms and Signaling
- Meningioma and schwannoma management
- Neuroinflammation and Neurodegeneration Mechanisms
- Fetal and Pediatric Neurological Disorders
- Circular RNAs in diseases
- ATP Synthase and ATPases Research
- Teratomas and Epidermoid Cysts
- Cancer Genomics and Diagnostics
University of Michigan
2018-2024
Mayo Clinic
2020-2022
WinnMed
2022
Ann Arbor Center for Independent Living
2021
Michigan Medicine
2018-2020
Mayo Clinic in Florida
2020
Children's Center
2020
ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (IDH)-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We find ATRX binds regulatory elements of cell-cycle phase transition genes cells, there marked reduction Checkpoint Kinase 1 (CHEK1) expression with loss, leading early release G2/M entry after...
Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFRA alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism increased tumor accumulation dasatinib. performed dose-response, synergism, P-glycoprotein inhibition, pharmacokinetic studies vitro vivo human mouse models HGG. Six patients recurrent were treated everolimus. found effectively inhibited proliferation primary HGG cells...
Abstract Background H3K27M-mutant diffuse midline glioma (DMG) is a lethal brain tumor that usually occurs in children. Despite advances our understanding of its underlying biology, efficacious therapies are severely lacking. Methods We screened library drugs either FDA-approved or clinical trial using patient-derived DMG cell lines with viability as the outcome. Results were validated for relevance and mechanistic importance patient specimens from biopsy autopsy, lines, inhibition by gene...
Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis and limited understanding of the mechanism behind tumor invasion. Previous reports demonstrate upregulation protein ID1 H3K27M ACVR1 mutations in DMG, but this has not been confirmed human or therapeutically targeted.
Glioblastoma (GBM) during infancy is rare, and the clinical outcomes of congenital GBM are not well understood. Correspondingly, aim this study was to present a long-term survivor case from authors' institution, establish an integrated cohort cases across published literature better understand course disease in setting.
Abstract Diffuse midline gliomas (DMGs) are aggressive tumors characterized by infiltration into normal brain tissue, hindering surgical resection and contributing to overall morbidity mortality. We established a novel two-step pooled whole genome CRISPR-Migration screen using serum-free conditions laminin-dependent cell attachment, mimicking migration on vasculature scaffolds, common feature in glioblastoma (GBM). Comparing DMG GBM primary lines (n=5), genes involved focal adhesion (ITGB1,...
Abstract Infiltration into the brain tissue is one of main features diffuse midline gliomas (DMG), also characterized by histone mutation H3K27M and overall survival 12-15 months from diagnosis. To study which genes are critical for H3K27M-DMG tumor cell migration in brain, we established a novel two-step pooled whole genome CRISPR-Migration screen metastatic (n=3) glioblastoma (GBM, n=2) stem cells using serum-free conditions laminin-dependent attachment, mimicking on vasculature scaffolds....
Abstract ONC201, the first bitopic DRD2 antagonist for clinical oncology, has shown efficacy in H3 K27M-mutant glioma. We performed an integrated preclinical and analysis of ONC201 thalamic was effective mouse intra-uterine electroporation (IUE)-generated gliomas, with vitro IC50 500 nM 50% prolongation median survival vivo (p=0.02, n=14). Elevated expression found thalamus non-malignant brain tissue, leading to hypothesis that tumors may be a particularly ONC201-sensitive sub-group....
Abstract ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in H3 K27M-mutant glioma. Given that the thalamus highest extra-striatal expression of DRD2, we performed an integrated preclinical clinical analysis ONC201 thalamic was effective mouse intra-uterine electroporation (IUE)-generated gliomas, with vitro IC50 500 nM 50% prolongation median survival vivo (p=0.02, n=14). We analyzed glioma patients treated on active trials as 5/22/19 enrollment...
e13508 Background: Pediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. The CNS penetration of inhibitors, such as dasatinib, is limited by the tumor-efflux protein P-glycoprotein (P-gp). We hypothesized that co-treatment with everolimus, which has been shown to block P-gp, will increase efficacy dasatinib in vitro vivo models well human PDGFRA-driven glioma. Methods: Tumors were generated mice using an intra-uterine electroporation (IUE) model [introduction...
Abstract Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive brain tumor with rare survival beyond two years. This poor prognosis largely due to the tumor’s infiltrative and invasive nature. Previous reports demonstrate upregulation of transcription factor ID1 H3K27M ACVR1 mutations, but this has not been confirmed in human tumors or therapeutically targeted. We developed an utero electroporation (IUE) murine H3K27M-driven model, which demonstrates increased expression H3K27M-...
Abstract Background Pediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. We hypothesized that co-treatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven through combinatorial synergism increased tumor accumulation dasatinib. Methods Dose response, studies, P-gp inhibition pharmacokinetic studies were performed on vitro vivo human mouse models HGG. Six patients recurrent treated everolimus. Results Dasatinib effectively inhibited...
Abstract Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis. The mechanism behind tumor invasion is currently not well understood. Previous reports demonstrate upregulation of the protein ID1 H3K27M and ACVR1 mutations in DMG, but this has been confirmed human or therapeutically targeted. Whole exome, RNA, ChIP-sequencing were performed on locus DMG tissue. Scratch-assay migration transwell assays cultured cells following...
ATRX is a histone chaperone protein recurrently mutated in pediatric GBM. We previously confirmed its role tumor progression and mutational burden glioma. However, the mechanism which mediates proliferative advantage of loss GBM remains unexplained. Recent data revealed distinct pattern DNA binding sites using ChIP-seq mouse neuronal precursor cells (mNPCs). Using peaks identified p53-/- mNPCs, we that were significantly enriched gene promoters (p<0.0001) CpG islands compared with random...
Abstract Gliomas are a leading cause of cancer mortality in children and adults new targeted therapies desperately needed. ATRX is chromatin remodeling protein that recurrently mutated H3F3A-mutant pediatric GBM IDH-mutant grade 2/3 adult glioma. We previously showed loss glioma results tumor growth additional mutations. However, the mechanism driving these phenotypes has not been fully established. found ChIP-Seq datasets mouse neuronal precursor cells (NPCs) experimental models human...
Abstract Diffuse intrinsic pontine gliomas (DIPGs) are lethal brain tumors with no effective therapies other than radiation. Inhibitor of DNA binding (ID) proteins key regulators tissue and lineage-specific gene differentiation during embryogenesis. Previous work has shown that H3F3A ACVR1 mutations increase ID1 expression in cultured astrocytes, but this not been validated human DIPG, nor the regulation targetability explored DIPG. Analysis multi-focal post-mortem tumor normal (n=52) as...
Abstract Patients with diffuse midline glioma (DMG) harboring H3 K27M mutation rarely survive longer than two years and have no proven therapies following first-line radiation. ONC201, a bitopic DRD2 antagonist allosteric ClpP agonist, has shown encouraging efficacy in early phase studies K27M-mutant DMG. In order to define response rates DMG patients clarify the genomic, anatomic molecular predictors of response, we performed an integrated pre-clinical clinical analysis ONC201 treatment....
Abstract Diffuse intrinsic pontine gliomas (DIPGs) are lethal brain tumors with no effective therapies other than radiation. Inhibitor of DNA binding (ID) proteins, key regulators lineage commitment during embryogenesis, implicated in tumorigenesis multiple human cancers. Prior work showed that recurrent H3F3A and ACVR1 mutations increase ID1 expression cultured astrocytes. However, this has not been validated DIPG. The regulation targetability DIPG explored either. Exome transcriptome...
Abstract Gliomas are a leading cause of cancer mortality in children and adults, new targeted therapies desperately needed. ATRX is chromatin remodeling protein that recurrently mutated H3F3A-mutant pediatric glioblastoma (GBM) IDH-mutant grade 2/3 adult glioma. We previously showed loss glioma results tumor growth additional mutations. However, the mechanism driving these phenotypes has not been fully established. found ChIP-Seq/ChIP-qPCR mouse neuronal precursor cells (NPCs) GBM with...
Abstract BACKGROUND Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with no curative therapies. Inhibitor of DNA binding (ID) proteins key regulators gene differentiation during embryogenesis. Previous work has shown that H3F3A and ACVR1 mutations increase ID1 expression in cultured astrocytes, but this not been validated human DIPG, nor the regulation targetability explored DIPG. RESULTS Analysis post-mortem tissue multiple datasets showed to be elevated...
Abstract Patients with diffuse midline glioma (DMG) harboring H3 K27M mutation have no proven therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has induced early responses in patients K27M-mutant DMG. We performed an integrated pre-clinical clinical assessment of ONC201 treatment, order to define response rates DMG clarify predictors response. was effective murine gliomas excellent CNS penetration survival benefit. treated on active trials (n=50) showed...