Publications

@article{Kocon2025-ay,

title = {Regional profiling reveals a distinct glioblastoma infiltrative  margin proteome},

author = {Artur Kocon and Stuart J Smith and Benito Morentin and Luis F Callado and Wayne Carter and Ruman Rahman},

doi = {10.1038/s41598-025-09228-z},

year  = {2025},

date = {2025-07-01},

urldate = {2025-07-01},

journal = {Sci. Rep.},

volume = {15},

number = {1},

pages = {24021},

publisher = {Springer Science and Business Media LLC},

abstract = {Isocitrate dehydrogenase wild-type glioblastoma, a malignant 

 brain tumour of glial origin, confers a poor prognosis with a 

 median survival of 12 to 16 months from diagnosis. Glioblastomas 

 are aggressive tumours that rapidly proliferate and diffusely 

 infiltrate surrounding brain tissue. Current multimodal standard 

 treatment is typically ineffective and despite gross total 

 surgical resection, tumours recur with more aggressive 

 sub-clonal populations of malignant cells. A defining 

 characteristic of glioblastoma is its highly heterogeneous 

 nature and acquirement of somatic mutations advantageous to 

 tumour growth and suppression of apoptotic pathways. 

 Pathogenesis of malignant brain tumours as well as its mode of 

 transformation to a more aggressive subtype is still largely 

 unknown. Although genomic studies have elucidated a plethora of 

 genetic markers associated with glioblastoma subtypes, only a 

 few have been utilised in a clinical setting. One of the 

 emerging approaches to studying glioblastomas is by 

 investigating how an active proteome contributes to its 

 aggressive nature. Furthermore, through activation of specific 

 pathways via post-translational modifications of proteins such 

 as phosphorylation, glioblastomas create an intricate network of 

 signalling pathways which favour tumour growth and 

 proliferation. Here, we investigated the feasibility of diverse 

 methodological approaches to describe abnormal protein 

 signalling across distinct intra-tumour regions of primary 

 glioblastoma tissue, including proliferative core, peripheral 

 rim, and invasive margin. Whilst we observe a broadly comparable 

 proteome relative to the human non-diseased brain, we identify 

 cytoplasmic proteins α-trypsin, actin, apolipoprotein A1 

 and transthyretin which may putatively be associated with the 

 GBM infiltrative tumour margin.},

keywords = {2D-PAGE, Glioblastoma, Proteomics, Tandem mass spectrometry},

pubstate = {published},

tppubtype = {article}

}

@article{Thomas2025-td,

title = {Evolution of preclinical models for glioblastoma modelling and drug screening},

author = {Grace Thomas and Ruman Rahman},

doi = {10.1007/s11912-025-01672-4},

year  = {2025},

date = {2025-05-01},

urldate = {2025-05-01},

journal = {Curr. Oncol. Rep.},

volume = {27},

number = {5},

pages = {601\textendash624},

publisher = {Springer Science and Business Media LLC},

abstract = {PURPOSE OF REVIEW: Isocitrate dehydrogenase wild-type 

 glioblastoma is an extremely aggressive and fatal primary brain 

 tumour, characterised by extensive heterogeneity and diffuse 

 infiltration of brain parenchyma. Despite multimodal treatment 

 and diverse research efforts to develop novel therapies, there 

 has been limited success in improving patient outcomes. 

 Constructing physiologically relevant preclinical models is 

 essential to optimising drug screening processes and identifying 

 more effective treatments. RECENT FINDINGS: Traditional in-vitro 

 models have provided critical insights into glioblastoma 

 pathophysiology; however, they are limited in their ability to 

 recapitulate the complex tumour microenvironment and its 

 interactions with surrounding cells. In-vivo models offer a more 

 physiologically relevant context, but often do not fully 

 represent human pathology, are expensive, and time-consuming. 

 These limitations have contributed to the low translational 

 success of therapies from trials to clinic. Organoid and 

 glioblastoma-on-a-chip technology represent significant advances 

 in glioblastoma modelling and enable the replication of key 

 features of the human tumour microenvironment, including its 

 structural, mechanical, and biochemical properties. Organoids 

 provide a 3D system that captures cellular heterogeneity and 

 tumour architecture, while microfluidic chips offer dynamic 

 systems capable of mimicking vascularisation and nutrient 

 exchange. Together, these technologies hold tremendous potential 

 for high throughput drug screening and personalised, precision 

 medicine. This review explores the evolution of preclinical 

 models in glioblastoma modelling and drug screening, emphasising 

 the transition from traditional systems to more advanced 

 organoid and microfluidic platforms. Furthermore, it aims to 

 evaluate the advantages and limitations of both traditional and 

 next-generation models, investigating their combined potential 

 to address current challenges by integrating complementary 

 aspects of specific models and techniques.},

keywords = {Glioblastoma, Glioblastoma-on-a-chip, Microfluids, Organoids, Preclinical model},

pubstate = {published},

tppubtype = {article}

}

@article{Wood2025-dw,

title = {Metabolomic characterisation of the glioblastoma invasive margin  reveals a region-specific signature},

author = {James Wood and Stuart J Smith and Marcos Castellanos-Uribe and Anbarasu Lourdusamy and Sean T May and David A Barrett and Richard G Grundy and Dong-Hyun Kim and Ruman Rahman},

doi = {10.1016/j.heliyon.2024.e41309},

year  = {2025},

date = {2025-01-01},

urldate = {2025-01-01},

journal = {Heliyon},

volume = {11},

number = {1},

pages = {e41309},

publisher = {Elsevier BV},

abstract = {Isocitrate dehydrogenase wild-type glioblastoma (GBM) is 

 characterised by a heterogeneous genetic landscape resulting 

 from dynamic competition between tumour subclones to survive 

 selective pressures. Improvements in metabolite identification 

 and metabolome coverage have led to increased interest in 

 clinically relevant applications of metabolomics. Here, we use 

 liquid chromatography-mass spectrometry and gene expression 

 microarray to profile integrated intratumour metabolic 

 heterogeneity, as a direct functional readout of adaptive 

 responses of subclones to the tumour microenvironment. 

 Multi-region surgical sampling was performed on five adult GBM 

 patients based on pre-operative brain imaging and 

 fluorescence-guided surgery. Polar and hydrophobic metabolites 

 extracted from tumour fragments were assessed, followed by 

 putative assignment of metabolite identifications based on 

 retention times and molecular mass. Class discrimination between 

 tumour regions through showed clear separation of tumour regions 

 based on polar metabolite profiles. Metabolic pathway 

 assignments revealed several significantly altered metabolites 

 between the tumour core and invasive region to be associated 

 with purine and pyrimidine metabolism. This proof-of-principle 

 study assesses intratumour heterogeneity through mass 

 spectrometry-based metabolite profiling of multi-region 

 biopsies. Bioinformatic interpretation of the GBM metabolome has 

 highlighted the invasive region to be biologically distinct 

 compared to tumour core and revealed putative drug-targetable 

 metabolic pathways associated with purine and pyrimidine 

 metabolism.},

keywords = {Glioblastoma, Invasive margin, Liquid-chromatography mass   spectrometry, Metabolomics},

pubstate = {published},

tppubtype = {article}

}

@article{Sanchez2024-rv,

title = {Radiogenomics as an integrated approach to glioblastoma  precision medicine},

author = {Isabella Sanchez and Ruman Rahman},

doi = {10.1007/s11912-024-01580-z},

year  = {2024},

date = {2024-10-01},

urldate = {2024-10-01},

journal = {Curr. Oncol. Rep.},

volume = {26},

number = {10},

pages = {1213\textendash1222},

publisher = {Springer Science and Business Media LLC},

abstract = {PURPOSE OF REVIEW: Isocitrate dehydrogenase wild-type 

 glioblastoma is the most aggressive primary brain tumour in 

 adults. Its infiltrative nature and heterogeneity confer a 

 dismal prognosis, despite multimodal treatment. Precision 

 medicine is increasingly advocated to improve survival rates in 

 glioblastoma management; however, conventional neuroimaging 

 techniques are insufficient in providing the detail required for 

 accurate diagnosis of this complex condition. RECENT FINDINGS: 

 Advanced magnetic resonance imaging allows more comprehensive 

 understanding of the tumour microenvironment. Combining 

 diffusion and perfusion magnetic resonance imaging to create a 

 multiparametric scan enhances diagnostic power and can overcome 

 the unreliability of tumour characterisation by standard 

 imaging. Recent progress in deep learning algorithms establishes 

 their remarkable ability in image-recognition tasks. Integrating 

 these with multiparametric scans could transform the diagnosis 

 and monitoring of patients by ensuring that the entire tumour is 

 captured. As a corollary, radiomics has emerged as a powerful 

 approach to offer insights into diagnosis, prognosis, treatment, 

 and tumour response through extraction of information from 

 radiological scans, and transformation of these tumour 

 characteristics into quantitative data. Radiogenomics, which 

 links imaging features with genomic profiles, has exhibited its 

 ability in characterising glioblastoma, and determining 

 therapeutic response, with the potential to revolutionise 

 management of glioblastoma. The integration of deep learning 

 algorithms into radiogenomic models has established an 

 automated, highly reproducible means to predict glioblastoma 

 molecular signatures, further aiding prognosis and targeted 

 therapy. However, challenges including lack of large cohorts, 

 absence of standardised guidelines and the \'black-box\' nature of 

 deep learning algorithms, must first be overcome before this 

 workflow can be applied in clinical practice.},

keywords = {Deep learning, Glioblastoma, Neuroimaging, Precision medicine, Radiogenomics, Radiomics},

pubstate = {published},

tppubtype = {article}

}

@article{Andrieux2023-pw,

title = {Spatially resolved transcriptomic profiles reveal unique 

 defining molecular features of infiltrative 5ALA-metabolizing 

 cells associated with glioblastoma recurrence},

author = {Geoffroy Andrieux and Tonmoy Das and Michaela Griffin and Jakob Straehle and Simon M L Paine and J\"{u}rgen Beck and Melanie Boerries and Dieter H Heiland and Stuart J Smith and Ruman Rahman and Sajib Chakraborty},

year  = {2023},

date = {2023-07-01},

journal = {Genome Med.},

volume = {15},

number = {1},

pages = {48},

publisher = {Springer Science and Business Media LLC},

abstract = {BACKGROUND: Spatiotemporal heterogeneity originating from 

 genomic and transcriptional variation was found to contribute to 

 subtype switching in isocitrate dehydrogenase-1 wild-type 

 glioblastoma (GBM) prior to and upon recurrence. 

 Fluorescence-guided neurosurgical resection utilizing 

 5-aminolevulinic acid (5ALA) enables intraoperative 

 visualization of infiltrative tumors outside the magnetic 

 resonance imaging contrast-enhanced regions. The cell population 

 and functional status of tumor responsible for enhancing 

 5ALA-metabolism to fluorescence-active PpIX remain elusive. The 

 close spatial proximity of 5ALA-metabolizing (5ALA +) cells to 

 residual disease remaining post-surgery renders 5ALA + biology 

 an early a priori proxy of GBM recurrence, which is poorly 

 understood. METHODS: We performed spatially resolved bulk RNA 

 profiling (SPRP) analysis of unsorted Core, Rim, Invasive margin 

 tissue, and FACS-isolated 5ALA + /5ALA - cells from the invasive margin across IDH-wt GBM patients (N = 10) coupled with 

 histological, radiographic, and two-photon excitation 

 fluorescence microscopic analyses. Deconvolution of SPRP 

 followed by functional analyses was performed using CIBEROSRTx 

 and UCell enrichment algorithms, respectively. We further 

 investigated the spatial architecture of 5ALA + enriched regions 

 by analyzing spatial transcriptomics from an independent IDH-wt GBM cohort (N = 16). Lastly, we performed survival analysis 

 using Cox Proportinal-Hazards model on large GBM cohorts. 

 RESULTS: SPRP analysis integrated with single-cell and spatial 

 transcriptomics uncovered that the GBM molecular subtype 

 heterogeneity is likely to manifest regionally in a 

 cell-type-specific manner. Infiltrative 5ALA + cell 

 population(s) harboring transcriptionally concordant GBM and 

 myeloid cells with mesenchymal subtype, -active wound response, 

 and glycolytic metabolic signature, was shown to reside within 

 the invasive margin spatially distinct from the tumor core. The 

 spatial co-localization of the infiltrating MES GBM and myeloid 

 cells within the 5ALA + region indicates PpIX fluorescence can 

 effectively be utilized to resect the immune reactive zone 

 beyond the tumor core. Finally, 5ALA + gene signatures were 

 associated with poor survival and recurrence in GBM, signifying 

 that the transition from primary to recurrent GBM is not 

 discrete but rather a continuum whereby primary infiltrative 

 5ALA + remnant tumor cells more closely resemble the eventual 

 recurrent GBM. CONCLUSIONS: Elucidating the unique molecular and 

 cellular features of the 5ALA + population within tumor invasive 

 margin opens up unique possibilities to develop more effective 

 treatments to delay or block GBM recurrence, and warrants 

 commencement of such treatments as early as possible 

 post-surgical resection of the primary neoplasm.},

keywords = {5ALA, Glioblastoma, Glycolysis, Mesenchymal subtype, Myeloid, Recurrence, Spatial transcriptomics, Wound response},

pubstate = {published},

tppubtype = {article}

}

@article{McCrorie2022-ls,

title = {Detection of label-free drugs within brain tissue using orbitrap 

 secondary ion mass spectrometry as a complement to 

 neuro-oncological drug delivery},

author = {Phoebe McCrorie and Jonathan Rowlinson and David J Scurr and Maria Marlow and Ruman Rahman},

year  = {2022},

date = {2022-03-01},

journal = {Pharmaceutics},

volume = {14},

number = {3},

pages = {571},

publisher = {MDPI AG},

abstract = {Historically, pre-clinical neuro-oncological drug delivery 

 studies have exhaustively relied upon overall animal survival as 

 an exclusive measure of efficacy. However, with no adopted 

 methodology to both image and quantitate brain parenchyma 

 penetration of label-free drugs, an absence of efficacy 

 typically hampers clinical translational potential, rather than 

 encourage re-formulation of drug compounds using nanocarriers to 

 achieve greater tissue penetration. OrbiSIMS, a next-generation 

 analytical instrument for label-free imaging, combines the high 

 resolving power of an OrbiTrapTM mass spectrometer with the 

 relatively high spatial resolution of secondary ion mass 

 spectrometry. Here, we develop an ex vivo pipeline using 

 OrbiSIMS to accurately detect brain penetration of drug 

 compounds. Secondary ion spectra were acquired for a panel of 

 drugs (etoposide, olaparib, gemcitabine, vorinostat and 

 dasatinib) under preclinical consideration for the treatment of 

 isocitrate dehydrogenase-1 wild-type glioblastoma. Each drug 

 demonstrated diagnostic secondary ions (all present molecular 

 ions [M-H]− which could be discriminated from brain analytes 

 when spiked at \>20 µg/mg tissue. Olaparib/dasatinib and 

 olaparib/etoposide dual combinations are shown as exemplars for 

 the capability of OrbiSIMS to discriminate distinct drug ions 

 simultaneously. Furthermore, we demonstrate the imaging 

 capability of OrbiSIMS to simultaneously illustrate label-free 

 drug location and brain chemistry. Our work encourages the 

 neuro-oncology community to consider mass spectrometry imaging 

 modalities to complement in vivo efficacy studies, as an 

 analytical tool to assess brain distribution of systemically 

 administered drugs, or localised brain penetration of drugs 

 released from micro- or nano-scale biomaterials.},

keywords = {Drug delivery, Glioblastoma, mass spectrometry imaging, OrbiSIMS},

pubstate = {published},

tppubtype = {article}

}

@article{Bastiancich2021-ob,

title = {Rationally designed drug delivery systems for the local 

 treatment of resected glioblastoma},

author = {Chiara Bastiancich and Alessio Malfanti and V\'{e}ronique Pr\'{e}at and Ruman Rahman},

year  = {2021},

date = {2021-10-01},

journal = {Adv. Drug Deliv. Rev.},

volume = {177},

number = {113951},

pages = {113951},

publisher = {Elsevier BV},

abstract = {Glioblastoma (GBM) is a particularly aggressive brain cancer 

 associated with high recurrence and poor prognosis. The standard 

 of care, surgical resection followed by concomitant radio- and 

 chemotherapy, leads to low survival rates. The local delivery of 

 active agents within the tumor resection cavity has emerged as 

 an attractive means to initiate oncological treatment 

 immediately post-surgery. This complementary approach bypasses 

 the blood-brain barrier, increases the local concentration at 

 the tumor site while reducing or avoiding systemic side effects. 

 This review will provide a global overview on the local 

 treatment for GBM with an emphasis on the lessons learned from 

 past clinical trials. The main parameters to be considered to 

 rationally design fit-of-purpose biomaterials and develop drug 

 delivery systems for local administration in the GBM resection 

 cavity to prevent the tumor recurrence will be described. The 

 intracavitary local treatment of GBM should i) use materials 

 that facilitate translation to the clinic; ii) be characterized 

 by easy GMP effective scaling up and easy-handling application 

 by the neurosurgeons; iii) be adaptable to fill the 

 tumor-resected niche, mold to the resection cavity or adhere to 

 the exposed brain parenchyma; iv) be biocompatible and possess 

 mechanical properties compatible with the brain; v) deliver a 

 therapeutic dose of rationally-designed or repurposed drug 

 compound(s) into the GBM infiltrative margin. Proof of concept 

 with high translational potential will be provided. Finally, 

 future perspectives to facilitate the clinical translation of 

 the local perisurgical treatment of GBM will be discussed.},

keywords = {Brain cancer, Controlled drug delivery, Glioblastoma, Hydrogels, Local drug delivery, Nanomedicine},

pubstate = {published},

tppubtype = {article}

}