Biology subjects

Marshall, G. M.

Publications and source records attributed to Marshall, G. M..

5 recordsLinked to original sources

bioRxiv2026

Therapeutic targeting of MYC- and MYCN-driven medulloblastoma with a novel MYC degrader molecule

BackgroundMedulloblastoma (MB) is the most common malignant brain tumour in children, and aggressive subgroups are frequently driven by the oncoproteins MYC or MYCN. Direct therapeutic targeting of MYC/MYCN has been challenging because of their intrinsically disordered protein structures. The aim of this study was to determine whether novel SE486-11 analogues (UNSW-SCs) can therapeutically target MYC/MYCN-driven MB. MethodsThe anticancer activity of UNSW-SCs was assessed in MB cell lines with differential MYC/MYCN expression. Target engagement was evaluated using surface plasmon resonance and drug affinity responsive target stability assays. Blood-brain barrier penetration, MYC/MYCN protein degradation, cell cycle effects, apoptosis, DNA damage, and synergy with histone deacetylase (HDAC) inhibitors were examined. Therapeutic efficacy was evaluated in murine models of MYC- and MYCN-driven human MB. ResultsUNSW-SCs showed potent anticancer activity, with preferential selectivity toward MB cells expressing high MYC/MYCN levels and IC50 values ranging from 0.22 to 1.18 M. The lead molecule, UNSW-SC-22, directly bound MYC, crossed the blood-brain barrier, and achieved a brain-to-plasma ratio of 1.44 at peak concentrations. UNSW-SC-22 induced MYC/MYCN-dependent cytotoxicity associated with enhanced proteasomal degradation, cell cycle arrest, apoptosis, and DNA damage. Combined treatment with HDAC inhibitors further reduced MYC/MYCN protein levels, increased DNA damage, and enhanced apoptosis. In vivo, UNSW-SC-22, either alone or with entinostat, significantly suppressed intracranial tumour growth and prolonged survival. ConclusionsUNSW-SC-22 is a brain-penetrant MYC/MYCN-targeting molecule with potent preclinical activity in MYC/MYCN-driven MB, supporting its development as a monotherapy or combination strategy with HDAC inhibition. Key PointsO_LIUNSW-SC-22 directly targets MYC/MYCN in medulloblastoma. C_LIO_LIUNSW-SC-22 crosses the blood-brain barrier and prolongs survival. C_LIO_LIHDAC inhibition enhances UNSW-SC-22 activity in MYC-driven cells. C_LI Importance of the StudyMYC- and MYCN-driven medulloblastomas remain among the most aggressive paediatric brain tumours, yet direct pharmacological targeting of MYC/MYCN has historically been difficult. This study identifies UNSW-SC-22 as a novel brain-penetrant small molecule that directly engages MYC/MYCN and promotes proteasomal degradation, leading to tumour cell death. Compared with prior MYC-directed approaches, UNSW-SC-22 combines direct target engagement, blood-brain barrier penetration, and in vivo efficacy in orthotopic MYC- and MYCN-driven medulloblastoma models. The study further demonstrates that combining UNSW-SC-22 with histone deacetylase inhibition enhances MYC/MYCN suppression, DNA damage, apoptosis, and survival benefit. These findings provide a translational framework for developing MYC/MYCN degradation as a therapeutic strategy for high-risk medulloblastoma and support future pharmacological optimisation, biomarker-guided patient selection, and combination therapy development.

cancer biology↗

bioRxiv2025

Expanding the utility of transcriptome analysis for mutation detection in high-risk childhood precision oncology

In precision oncology, whole transcriptome sequencing (RNA-seq) excels at identifying oncogenic fusions. Here, using a cohort of 477 high-risk paediatric tumours, we demonstrate that RNA-seq can identify all mutation classes found previously using whole genome sequencing (WGS) and provides additional functional insights into their pathogenicity. By incorporating reference-guided fusion, and reference-free structural variant (SV) detection algorithms with RNA abundance assessment, RNA-seq identified 96% of SVs and resolved 33 complex SVs that WGS failed to identify. Furthermore, RNA-seq identified 92% of all single nucleotide variants and small insertions and deletions. Importantly RNA-seq informed the pathogenicity assessment in 22% of variants through identification of allele specific expression or the functional consequence of splice-altering variants. The utility of RNA-seq extends beyond fusion identification to the interpretation of mutation pathogenicity and the discovery of important mutations that would otherwise go undetected. We propose that RNA-seq is an indispensable companion to WGS in precision medicine.

genomics↗

bioRxiv2022

A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer

Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. We combined immunohistochemistry (IHC) and molecular profiling to develop an alternative, expression-based signature associated with CD8+ T-cell infiltration of the TIME in high-risk paediatric tumours. Using this novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.

cancer biology↗

bioRxiv2020

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

Peripheral neuroblastic tumors (PNTs) are the most common extracranial solid tumors in early childhood. They represent a spectrum of neural crest derived tumors including neuroblastoma, ganglioneuroblastoma and ganglioneuroma. PNTs exhibit heterogeneity due to interconverting malignant cell states described as adrenergic/nor-adrenergic or mesenchymal/neural crest cell in origin. The factors determining individual patient levels of tumor heterogeneity, their impact on the malignant phenotype, and the presence of other cell states are unknown. Here, single-cell RNA-sequencing analysis of 4267 cells from 7 PNTs demonstrated extensive transcriptomic heterogeneity. Trajectory modelling showed that malignant neuroblasts move between adrenergic and mesenchymal cell states via a novel state that we termed a "transitional" phenotype. Transitional cells are characterized by gene expression programs linked to a sympathoadrenal development, and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature was highly predictive of poor prognosis when compared to adrenergic and mesenchymal expression patterns. High transitional gene expression in neuroblastoma cell lines identified a similar transitional H3K27-acetylation super-enhancer landscape, supporting the concept that PNTs have phenotypic plasticity and transdifferentiation capacity. Additionally, examination of PNT microenvironments, found that neuroblastomas contained low immune cell infiltration, high levels of non-inflammatory macrophages, and low cytotoxic T lymphocyte levels compared with more benign PNT subtypes. Modeling of cell-cell signaling in the tumor microenvironment predicted specific paracrine effects toward the various subtypes of malignant cells, suggesting further cell-extrinsic influences on malignant cell phenotype. Collectively, our study reveals the presence of a previously unrecognized transitional cell state with high malignant potential and an immune cell architecture which serve both as potential biomarkers and therapeutic targets.

cancer biology↗

bioRxiv2019

Genomic landscape of 261 childhood cancer patient-derived xenograft models

Accelerating cures for children with cancer remains an immediate challenge due to extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs) from high-risk childhood cancers, many refractory to current standard-of-care treatments. Here, we genomically characterize 261 PDX models from 29 unique pediatric cancer malignancies and demonstrate faithful recapitulation of histologies, subtypes, and refine our understanding of relapsed disease. Expression and mutational signatures are used to classify tumors for TP53 and NF1 inactivation, as well as impaired DNA repair. We anticipate that these data will serve as a resource for pediatric oncology drug development and guide rational clinical trial design for children with cancer.\n\nHighlightsO_LIMultiplatform genomic analysis defines landscape of 261 pediatric cancer patient derived xenograft (PDX) models\nC_LIO_LIPediatric patient derived xenografts faithfully recapitulate relapsed disease\nC_LIO_LIInferred TP53 pathway inactivation correlates with pediatric cancer copy number burden\nC_LIO_LISomatic mutational signatures predict impaired DNA repair across multiple histologies\nC_LI

genomics↗