A5009984010- PARP inhibition in cancer therapy
- Neuroblastoma Research and Treatments
- Cancer therapeutics and mechanisms
- Glycosylation and Glycoproteins Research
- CRISPR and Genetic Engineering
- Protein Degradation and Inhibitors
- Endoplasmic Reticulum Stress and Disease
- Chemical Reactions and Isotopes
- Cancer Research and Treatments
- Enzyme Structure and Function
- Science, Research, and Medicine
- Glioma Diagnosis and Treatment
- Lysosomal Storage Disorders Research
- Electric Motor Design and Analysis
- Galectins and Cancer Biology
- Computational Drug Discovery Methods
- Ubiquitin and proteasome pathways
- Cancer Genomics and Diagnostics
- Zebrafish Biomedical Research Applications
- 14-3-3 protein interactions
- Carbohydrate Chemistry and Synthesis
- ATP Synthase and ATPases Research
- Magnetic Properties and Applications
- Protein Structure and Dynamics
- Cutaneous lymphoproliferative disorders research
UNSW Sydney
2023-2025
Children's Cancer Institute Australia
2024-2025
Cancer Institute of New South Wales
2023-2024
University of Leicester
2019-2024
Cancer Institute (WIA)
2024
Abstract For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result a therapeutic recommendation. To identify potential strategies for treating these high-risk patients, we performed vitro screening 125 patient-derived samples against library 126 anticancer drugs. Tumor cell expansion did influence drug responses, and 82% the screens on expanded tumor cells were completed while still under clinical care. High-throughput (HTS)...
Abstract Endoplasmic reticulum (ER) retention of misfolded glycoproteins is mediated by the ER‐localized eukaryotic glycoprotein secretion checkpoint, UDP‐glucose glucosyl‐transferase (UGGT). The enzyme recognizes a and flags it for ER re‐glucosylating one its N ‐linked glycans. In background congenital mutation in secreted gene, UGGT‐mediated can cause rare disease, even if mutant retains activity (“responsive mutant”). Using confocal laser scanning microscopy, we investigated here...
The ERAD glycoprotein misfolding checkpoint complex de-mannosylates misfolded glycoproteins to enable retrotranslocation, ubiquitination, and proteasomal degradation. comprises an Endoplasmic Reticulum-Degradation Enhancing α-Mannosidase (EDEM) a Protein Disulfide Isomerase (PDI). We solved Cryo-EM structures of Chaetomium thermophilum ( Ct ) CtEDEM:CtPDI, both as the heterodimer with no client in α1-antitrypsin (A1AT-NHK). EDEM catalytic domain nests within PDI arc, while A1AT-NHK binds...
<title>Abstract</title> The ERAD glycoprotein misfolding checkpoint complex de-mannosylates misfolded glycoproteins targeting them to retrotranslocation, ubiquitination, and proteasomal degradation. comprises an Endoplasmic Reticulum-Degradation Enhancing α-Mannosidase (EDEM) a Protein Disulfide Isomerase (PDI). We solved Cryo-EM structures of the Chaetomium thermophilum (Ct) EDEM:PDI complex, both by itself in with classic substrate, α1-antitrypsin (A1AT-NHK). EDEM catalytic domain nestles...
<title>Abstract</title> Precision medicine programs like the Zero Childhood Cancer Program perform comprehensive molecular analysis of patient tumors, enabling detection novel structural variants that may be cryptic to standard techniques. Identification these can impact individual treatment, and beyond this establish new mechanisms oncogenic activation. We have identified a internal tandem duplication (ITD) in receptor tyrosine kinase (RTK), <italic>NTRK2</italic>, with FOXR2-activated CNS...
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy with median survival of 14 months (with window 6–28 months) from diagnosis.1 BPDCN derived the precursors cells2 recognized as an independent entity myeloid neoplasms in 2016 updated World Health Organization classification.3 Although predominantly affects adults age 70s, cases involving younger children have been reported. Unique clinical presentations include skin infiltration, at...
UDP-glucose:glycoprotein glucosyltransferase (UGGT) flags misfolded glycoproteins for ER retention. We report crystal structures of full-length Chaetomium thermophilum UGGT (CtUGGT), two CtUGGT double-cysteine mutants, and its TRXL2 domain truncation (CtUGGT-ΔTRXL2). molecular dynamics (MD) simulations capture extended conformations reveal clamping, bending, twisting inter-domain movements. name "Parodi limit" the maximum distance on same glycoprotein between a site misfolding an N-linked...
Abstract BACKGROUND The utility of precision-guided therapeutic approaches to H3K27-altered diffused midline glioma (DMG) remains uncertain. Australian Zero Childhood Cancer (ZERO) program combines molecular profiling (whole-genome sequencing (WGS), whole-transcriptome (RNAseq), and DNA methylation profiling), with in vitro high-throughput drug screening (HTS) patient-derived xenograft (PDX) drug-efficacy testing patients high-risk cancer. METHODS We report on the cohort enrolled a DMG ZERO...
Abstract The Australian Zero Childhood Cancer (ZERO) program and German INFORM registry - the largest precision medicine initiatives for childhood cancers conduct comprehensive tumour molecular characterisation ex vivo drug sensitivity profiling (DSP) to support clinical treatment decision-making. Both programs have identified frequent alterations in mitogen-activated protein kinase (MAPK) pathway, leading recommendation of with a (MEK) inhibitor. Interestingly, DSP indicates that tumors...
Abstract Personalized medicine programs, including the Zero Childhood Cancer Program (ZERO), perform molecular analysis of individual patient tumours to identify targets for therapy. The comprehensive and unbiased sequencing approaches used by ZERO, whole genome (WGS) RNA (RNAseq), enables detection novel structural variants (SVs) that may be cryptic standard cytogenetic techniques or panel approaches. Identification Receptor Tyrosine Kinase (RTK) activating in paediatric cancers, example...
Abstract Personalized medicine is revolutionizing cancer detection, characterization, and treatment, however, 30% of children with high-risk cancers lack an actionable molecular target need alternate approaches to identify personalized treatment recommendations. While mouse patient-derived xenografts (PDXs) are widely regarded as the gold standard for preclinical drug response prediction, they remain highly resource-intensive, challenging establish, often have establishment times outside...
Abstract Precision medicine for paediatric and adult cancers that includes drug sensitivity profiling, can identify effective therapies individual patients. However, obtaining adequate biopsy samples high-throughput (HTP) screening remains challenging, with tumours needing to be expanded in culture or patient-derived xenografts – this is time-consuming often unsuccessful. Herein, we have developed tumour models using an engineered extracellular matrix (ECM) tissue mimic hydrogel system HTP...
UDP-glucose: glycoprotein glucosyltransferase (UGGT) is the folding checkpoint in eukaryotic secretory pathway. The enzyme detects misfolded glycoproteins Endoplasmic Reticulum, and flags them for retention by re-glucosylating on an N-linked glycan. fit of a UGGT crystal structure to negative stain electron microscopy reconstruction complex with antibody suggests that misfold-sensing N-terminal portion its C-terminal catalytic domain are tightly associated. Molecular Dynamics (MD)...
Summary UDP-glucose:glycoprotein glucosyltransferase (UGGT) is the only known glycoprotein folding quality control checkpoint in eukaryotic secretory pathway. When enzyme detects a misfolded Endoplasmic Reticulum (ER), it dispatches for ER retention by re-glucosylating on one of its N-linked glycans. Recent crystal structures fungal UGGT have suggested conformationally mobile. Here, negative stain electron microscopy reconstruction complex with monoclonal antibody confirms that...
Endoplasmic reticulum (ER) retention of mis-folded glycoproteins is mediated by the ERlocalised eukaryotic glycoprotein secretion checkpoint, UDP-glucose glucosyl-transferase (UGGT). The enzyme recognises a and flags it for ER reglucosylating one its N-linked glycans. In background congenital mutation in secreted gene, UGGT-mediated can cause rare disease even if mutant retains activity ("responsive mutant"). Here, we investigated subcellular localisation human Trop-2 Q118E variant, which...
<div>Abstract<p>For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result a therapeutic recommendation. To identify potential strategies for treating these high-risk patients, we performed <i>in vitro</i> screening 125 patient-derived samples against library 126 anticancer drugs. Tumor cell expansion did influence drug responses, and 82% the screens on expanded tumor cells were completed while still...
<div>Abstract<p>For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result a therapeutic recommendation. To identify potential strategies for treating these high-risk patients, we performed <i>in vitro</i> screening 125 patient-derived samples against library 126 anticancer drugs. Tumor cell expansion did influence drug responses, and 82% the screens on expanded tumor cells were completed while still...
<p>Supplementary Figures</p>
<p>Supplementary Figures</p>
<p>Supplementary Figures</p>
<div>Abstract<p>For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result a therapeutic recommendation. To identify potential strategies for treating these high-risk patients, we performed <i>in vitro</i> screening 125 patient-derived samples against library 126 anticancer drugs. Tumor cell expansion did influence drug responses, and 82% the screens on expanded tumor cells were completed while still...
<p>Supplementary Figures</p>