Izac J. Findlay
A5002062212- Glioma Diagnosis and Treatment
- ATP Synthase and ATPases Research
- Neuroblastoma Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Advanced Proteomics Techniques and Applications
- Mass Spectrometry Techniques and Applications
- Circular RNAs in diseases
- Brain Tumor Detection and Classification
- Metabolomics and Mass Spectrometry Studies
- Acute Myeloid Leukemia Research
- Cancer Research and Treatments
- Immune cells in cancer
- Mitochondrial Function and Pathology
- Epigenetics and DNA Methylation
- Advanced biosensing and bioanalysis techniques
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- PARP inhibition in cancer therapy
- Ferroptosis and cancer prognosis
- Cancer, Stress, Anesthesia, and Immune Response
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Single-cell and spatial transcriptomics
- Acute Lymphoblastic Leukemia research
- Neuroinflammation and Neurodegeneration Mechanisms
- Immune Cell Function and Interaction
University of Newcastle Australia
2021-2024
Hunter Medical Research Institute
2021-2024
Abstract Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized adults. Their potential heterogeneity at different ages and locations is vastly understudied. Here, through dissecting single-cell transcriptomic, epigenomic spatial architectures a comprehensive cohort patient H3-K27M DMGs, we delineate how age anatomical location shape glioma cell-intrinsic -extrinsic features light...
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is only established treatment, with median patient survival 9 to 11 months. ONC201 a DRD2 antagonist and ClpP agonist that has shown preclinical emerging clinical efficacy in DMG. However, further work needed identify mechanisms response DIPGs treatment determine whether recurring genomic features influence response. Using systems-biological approach,...
Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine – DIPG), are uniformly fatal brain that lack effective treatment. Analysis of CRISPR-Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across DIPG patient models, highlighting therapeutic potential blood-brain barrier penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At human equivalent maximum tolerated dose, mice treated with paxalisib...
Abstract Background Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem tumor for which radiation the only treatment. Case studies report clinical response to ONC201 patients with H3K27M-mutant gliomas. Oncoceutics (ONC201) available in United States and Japan; however, Germany, DIPG can be prescribed dispensed locally produced compound—ONC201 German-sourced (GsONC201). Pediatric oncologists face dilemma of supporting administration GsONC201 as conjecture surrounds its...
Mutations in the type III receptor tyrosine kinase FLT3 are frequent patients with acute myeloid leukemia (AML) and associated a poor prognosis. AML is characterized by overproduction of reactive oxygen species (ROS), which can induce cysteine oxidation redox-sensitive signaling proteins. Here, we sought to characterize specific pathways affected ROS assessing oncogenic primary samples. The or phosphorylation proteins that mediate growth proliferation was increased samples from patient...
Global high-throughput phosphoproteomic profiling is increasingly being applied to cancer specimens identify the oncogenic signaling cascades responsible for promoting disease initiation and progression; pathways that are often invisible genomics analysis. Hence, has enormous potential inform improve individualized anti-cancer treatment strategies. However, achieve adequate depth coverage necessary activated, hence, targetable kinases driving pathways, affinity phosphopeptide enrichment...
Abstract FLT3-mutations are diagnosed in 25-30% of patients with acute myeloid leukemia (AML) and associated a poor prognosis. AML is the overproduction reactive oxygen species (ROS), which drives genomic instability through oxidation DNA bases, promoting clonal evolution, treatment resistance outcomes. ROS also important second messengers, triggering cysteine redox sensitive signaling proteins, however, specific pathways influenced by remain enigmatic. Here we have surveyed...
Abstract BACKGROUND Diffuse midline glioma (DMG) is a devastating pediatric high-grade (pHGG) located along the structures of brain and spine. Palliative radiotherapy only approved treatment outside clinical trials, with patients given 9–11-months survival post-diagnosis. Over last 10-years, it has become common for to be prescribed precision therapies targeting genetic alterations, however largely, DMG harbor alterations that are untargetable. METHODS To improve patient outcomes, we...
Abstract BACKGROUND Less than 10% of patients with diffuse midline glioma (DMG) survive 2-years post-diagnosis, no approved treatments other palliative radiotherapy. Immune-checkpoint inhibition has failed in the clinic, likely due to a lack tumor infiltrating lymphocytes (TILs) and limited/no expression immune checkpoint proteins or proinflammatory cytokines microenvironment (TIME). Similarly, glioblastoma suffer from ‘cold’ TIME, linked sequestration T cells bone marrow (BM) through...
Abstract BACKGROUND Diffuse midline glioma (DMG) is a universally fatal CNS tumor, with median overall survival of <12-months. Recent studies, including our own, have identified overexpression the mitochondrial protease ClpP in DMG patient samples. plays pivotal role regulating energy production. Brain-penetrant agonists, ONC201, ONC206, and TR107, induce non-specific degradation electron transport chain. However, there considerable variability response cell lines to these therapies,...
ABSTRACT Alterations in the FMS-like tyrosine kinase 3 (FLT3) gene are most frequent driver mutations acute myeloid leukaemia (AML), linked to a high risk of relapse patients with internal tandem duplications (FLT3-ITD). Tyrosine inhibitors (TKIs) targeting FLT3 protein approved for clinical use, yet resistance often emerges. This is mainly seen following acquisition additional point domain (TKD), resulting double mutant FLT3-ITD/TKD, which sustains cell signalling and survival despite...
<p>All Supplementary Figures and their captions.</p>
<p>All Supplementary Tables</p>
<p>All Supplementary Figures and their captions.</p>
<p>All Supplementary Tables</p>
<div>Abstract<p>Diffuse midline gliomas (DMG), including diffuse intrinsic pontine (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is only established treatment, with median patient survival 9-11 months. ONC201 a DRD2 antagonist and ClpP agonist that has shown preclinical emerging clinical efficacy in DMG. However, further work needed to identify mechanisms response DIPGs treatment determine whether recurring genomic features influence response. Using...
Abstract Diffuse midline glioma (DMG), including diffuse intrinsic pontine (DIPG), are uniformly fatal brain cancers affecting children, adolescents, and young adults. These tumors characterized by ‘oncohistone’ mutations in histone H3 genes (H3F3A, HIST1H3B, HIST1H3C), resulting the substitution of lysine 27 to methionine (H3K27M), dominant negative hypomethylation at (H3K27) a global loss gene silencing. CRISPR-Cas9 loss-of-function deletion screens identified mutation-independent...
Abstract Histone 3 lysine27-to-methionine mutations (H3-K27M) frequently occur in childhood diffuse midline gliomas (DMGs) of the pons, thalamus, and spinal cord, presumed to be driven by specific spatiotemporal context these locations during postnatal development. While most common pons at mid-childhood ages, same oncohistone mutation is recurrently detected adult DMGs throughout different regions. The potential heterogeneity tumors ages anatomical are vastly understudied. Through...
Abstract Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine – DIPG), are uniformly fatal brain that lack effective pharmacological treatment. Analysis of pooled CRISPR-Cas9 loss-of-function gene deletion screen datasets, identified PIK3CA and MTOR as targetable molecular dependencies across DIPG patient derived models, highlighting therapeutic potential blood-brain barrier penetrant PI3K/Akt/mTOR inhibitor paxalisib. At human equivalent...
<p>All Supplementary Tables</p>
<p>All Supplementary Tables</p>