Publications by authors named "Javad Nazarian"

Background: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood central nervous system tumor. Diagnosis and monitoring of tumor response to therapy is based on magnetic resonance imaging (MRI). MRI-based analyses of tumor volume and appearance may aid in the prediction of patient overall survival (OS).

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Glioblastoma multiforme (GBM) is an aggressive and lethal form of brain cancer with few effective treatments. In this context, Zika virus has emerged as a promising therapeutic agent due to its ability to selectively infect and kill GBM cells. To elucidate these mechanisms and expand the landscape of oncolytic virotherapy, we pursued a transcriptomic meta-analysis comparing the molecular signatures of Zika infection in GBM and neuroblastoma (NBM).

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Pediatric cancers are the leading cause of disease-related deaths in children and adolescents. Most of these tumors are difficult to treat and have poor overall survival. Concerns have also been raised about drug toxicity and long-term detrimental side effects of therapies.

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  • Pediatric high-grade gliomas (pHGGs), particularly diffuse midline gliomas (DMGs), are highly aggressive tumors with low survival rates, yet the combination of Delta-24-RGD and ONC201 has shown potential for enhanced treatment efficacy.
  • In laboratory and mouse model studies, the combination treatment did not alter virus replication but demonstrated a synergistic or additive cytotoxic effect, leading to increased DNA damage and metabolic disruptions in tumor cells.
  • Additionally, the combination treatment improved survival rates in mice models and led to a shift in the tumor microenvironment towards a more proinflammatory state, indicating a stronger immune response against the tumors.
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  • Diffuse midline glioma (DMG), particularly DIPG, is a fatal brain tumor with no effective treatments, but recent studies identified PIK3CA and MTOR as promising targets for therapy.
  • The research demonstrates that combining the PI3K/Akt/mTOR inhibitor paxalisib with the antihyperglycemic drug metformin and the PKC inhibitor enzastaurin can enhance treatment efficacy and prolong survival in animal models.
  • Advanced techniques like spatial transcriptomics and ATAC-Seq were used to evaluate the effects on tumor biology, revealing significant changes that could support a clinically relevant combination therapy for DIPG.
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Diffuse intrinsic pontine gliomas (DIPGs) are deadly pediatric brain tumors, non-resectable due to brainstem localization and diffusive growth. Over 80% of DIPGs harbor a mutation in histone 3 (H3.3 or H3.

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Background Diffuse midline glioma (DMG) is a devastating pediatric brain tumor unresponsive to hundreds of clinical trials. Approximately 80% of DMGs harbor H3K27M oncohistones, which reprogram the epigenome to increase the metabolic profile of the tumor cells. Methods We have previously shown preclinical efficacy of targeting both oxidative phosphorylation and glycolysis through treatment with ONC201, which activates the mitochondrial protease ClpP, and paxalisib, which inhibits PI3K/mTOR, respectively.

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  • Metabolic changes in pediatric diffuse midline glioma are influenced by the H3K27M histone mutation, which activates oncogenic pathways.
  • The RAS pathway and ERK5 kinase are crucial for tumor growth in these gliomas, with ERK5 playing a key role in cell proliferation and glycolysis.
  • Targeting the ERK5-PFKFB3 signaling axis with multi-targeted drugs could be an effective treatment strategy for patients with this type of cancer.
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  • * The research successfully identifies unique epigenetic patterns and tumor-originating proteins in the plasma, allowing for better differentiation of DMG patients from healthy individuals and those with other cancers.
  • * The method requires only a small blood sample and shows strong correlation with traditional imaging and DNA assessment techniques, highlighting its potential for non-invasive monitoring and diagnosis of DMG.
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Article Synopsis
  • - Recent clinical trials for H3K27-altered diffuse midline gliomas (DMGs) are showing promising results, indicating potential advancements in treatment.
  • - The text identifies three key challenges: improving experimental models to include immune and brain-specific factors, fostering collaboration between researchers, clinicians, and the industry, and optimizing clinical processes like biopsy and drug delivery.
  • - Emphasizes that extensive collaboration is crucial for enhancing our understanding of DMGs, as well as improving diagnostics and therapies for these tumors.
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High-grade glioma (HGG) is the most common cause of cancer death in children and the most common primary central nervous system tumor in adults. While pediatric HGG was once thought to be biologically similar to the adult form of disease, research has shown these malignancies to be significantly molecularly distinct, necessitating distinct approaches to their clinical management. However, emerging data have shown shared molecular events in pediatric and adult HGG including the histone H3K27M mutation.

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  • Diffuse intrinsic pontine glioma (DIPG) is a serious brain tumor and is the most common cause of cancer deaths in kids.
  • Scientists found that a protein called TIM-3 is present in both the tumor cells and nearby cells, which may help the tumor grow.
  • By blocking TIM-3, they noticed that it helped some mice live longer and fight off the tumor, showing it could be a good target for new treatments for DIPG.
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Gliomas are the most common primary central nervous system (CNS) tumors and a major cause of cancer-related mortality in children (age <15 years), adolescents and young adults (AYA, ages 15-39 years), and adults (age >39 years). Molecular pathology has helped enhance the characterization of these tumors, revealing a heterogeneous and ever more complex group of malignancies. Recent molecular analyses have led to an increased appreciation of common genomic alterations prevalent across all ages.

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Recent genomic data points to a growing role for somatic mutations altering core histone and linker histone-encoding genes in cancer. However, the prevalence and the clinical and biological implications of histone gene mutations in malignant tumors remain incompletely defined. To address these knowledge gaps, we analyzed somatic mutations in 88 linker and core histone genes across 12,743 tumors from pediatric, adolescent and young adult (AYA), and adult cancer patients.

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Diffuse midline gliomas (DMGs) are devastating pediatric brain tumors recognized as the leading cause of cancer-related death in children. DMGs are high-grade gliomas (HGGs) diagnosed along the brain's midline. Euchromatin is the hallmark feature of DMG, caused by global hypomethylation of H3K27 either through point mutations in histone H3 genes (H3K27M), or by overexpression of the enhancer of zeste homolog inhibitory protein.

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Unlabelled: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies.

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Pediatric brain and spinal cancers are collectively the leading disease-related cause of death in children; thus, we urgently need curative therapeutic strategies for these tumors. To accelerate such discoveries, the Children's Brain Tumor Network (CBTN) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) created a systematic process for tumor biobanking, model generation, and sequencing with immediate access to harmonized data. We leverage these data to establish OpenPBTA, an open collaborative project with over 40 scalable analysis modules that genomically characterize 1,074 pediatric brain tumors.

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Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. DMGs are driven by histone-tail-mutation-mediated epigenetic dysregulation and partner mutations in genes controlling proliferation and migration. One result of this epigenetic and genetic landscape is the overexpression of LIN28B RNA binding protein.

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Background: The objective of this study was to determine the safety, tolerability, and distribution of MTX110 (aqueous panobinostat) delivered by convection-enhanced delivery (CED) in patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) who completed focal radiation therapy (RT).

Methods: Patients with DIPG (2-21 years) were enrolled after RT. CED of MTX110 combined with gadoteridol was completed across 7 dose levels (DL) (30-90 µM; volumes ranging from 3 mL to 2 consecutive doses of 6 mL).

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The molecular characteristics of pediatric brain tumors have not only allowed for tumor subgrouping but have led to the introduction of novel treatment options for patients with specific tumor alterations. Therefore, an accurate histologic and molecular diagnosis is critical for optimized management of all pediatric patients with brain tumors, including central nervous system embryonal tumors. We present a case where optical genome mapping identified a ZNF532::NUTM1 fusion in a patient with a unique tumor best characterized histologically as a central nervous system embryonal tumor with rhabdoid features.

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Unlabelled: Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG.

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Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG.

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