Imperial College London

ProfessorEricAboagye

Faculty of MedicineDepartment of Surgery & Cancer

Professor
 
 
 
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Contact

 

+44 (0)20 3313 3759eric.aboagye

 
 
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Assistant

 

Mrs Maureen Francis +44 (0)20 7594 2793

 
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Location

 

GN1Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

369 results found

Piletsky S, Piletska E, Poblocka M, Macip S, Jones D, Braga M, Cao T, Singh R, Spivey A, Aboagye E, Piletsky Set al., 2021, Snapshot imprinting: Rapid identification of cancer cell surface proteins and epitopes using molecularly imprinted polymers, Nano Today: an international rapid reviews journal, Vol: 41, Pages: 1-8, ISSN: 1748-0132

Proteomic mapping of cell surfaces is an invaluable tool for drug development and clinical diagnostics. This work describes a new ‘snapshot imprinting’ method designed to obtain proteomic maps of cell surfaces, with the aim of identifying cell surface markers and epitopes for diagnostic and therapeutic applications. The analysis of two cancer cell lines, HN5 and MDA-MB-468, is described herein as a proof of concept, along with the selective targeting of three identified epitopes of epidermal growth factor receptor using molecularly imprinted polymer nanoparticles. 438 proteins were identified using this technique, with 283 considered to be transmembrane or extracellular proteins. The major advantage of the molecular imprinting approach developed here is the ability to analyse cell surface proteins without tedious fractionation, affinity separation or labelling. We believe that this system of protein analysis may provide a basic molecular diagnostics toolbox for precise, personalised treatment of cancer and other diseases.

Journal article

Braga M, Leow CH, Gil JH, Teh JH, Carroll L, Long NJ, Tang M-X, Aboagye EOet al., 2021, Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach, PLOS ONE, Vol: 16, Pages: e0260186-e0260186

<jats:p>The C-X-C chemokine receptor 4 (CXCR4) is G protein-coupled receptor that upon binding to its cognate ligand, can lead to tumor progression. Several CXCR4-targeted therapies are currently under investigation, and with it comes the need for imaging agents capable of accurate depiction of CXCR4 for therapeutic stratification and monitoring. PET agents enjoy the most success, but more cost-effective and radiation-free approaches such as ultrasound (US) imaging could represent an attractive alternative. In this work, we developed a targeted microbubble (MB) for imaging of vascular CXCR4 expression in cancer. A CXCR4-targeted MB was developed through incorporation of the T140 peptide into the MB shell. Binding properties of the T140-MB and control, non-targeted MB (NT-MB) were evaluated in MDA-MB-231 cells where CXCR4 expression was knocked-down (via shRNA) through optical imaging, and in the lymphoma tumor models U2932 and SuDHL8 (high and low CXCR4 expression, respectively) by US imaging. PET imaging of [<jats:sup>18</jats:sup>F]MCFB, a tumor-penetrating CXCR4-targeted small molecule, was used to provide whole-tumor CXCR4 readouts. CXCR4 expression and microvessel density were performed by immunohistochemistry analysis and western blot. T140-MB were formed with similar properties to NT-MB and accumulated sensitively and specifically in cells according to their CXCR4 expression. In NOD SCID mice, T140-MB persisted longer in tumors than NT-MB, indicative of target interaction, but showed no difference between U2932 and SuDHL8. In contrast, PET imaging with [<jats:sup>18</jats:sup>F]MCFB showed a marked difference in tumor uptake at 40–60 min post-injection between the two tumor models (p&lt;0.05). <jats:italic>Ex vivo</jats:italic> analysis revealed that the large differences in CXCR4 expression between the two models are not reflected in the vascular compartment, where the MB are restricted; in fact, microvesse

Journal article

Teh JH, Braga M, Allott L, Barnes C, Hernandez-Gil J, Tang M-X, Aboagye EO, Long NJet al., 2021, A kit-based aluminium-[F-18]fluoride approach to radiolabelled microbubbles, CHEMICAL COMMUNICATIONS, Vol: 57, Pages: 11677-11680, ISSN: 1359-7345

Journal article

Aboagye E, Li Y, Inglese M, Dubash S, Barnes C, Brickute D, Costa Braga M, Wang N, Beckley A, Heinzmann K, Allot L, Lu H, Chen C, Fu R, Fu R, Carroll Let al., 2021, Consideration of metabolite efflux in radiolabelled choline kinetics, Pharmaceutics, Vol: 13, Pages: 1-18, ISSN: 1999-4923

Hypoxia is a complex microenvironmental condition known to regulate choline kinase α (CHKA) activity and choline transport through transcription factor hypoxia-inducible factor-1α (HIF-1α) and, therefore may confound uptake of choline radiotracer[18F]fluoromethyl-[1,2-2H4]-choline ([18 F]-D4-FCH). The aim of this study was to investigate how hypoxia affects choline radiotracer dynamics. Three underlying mechanisms by which hypoxiacould potentially alter the uptake of the choline radiotracer, [18 F]-D4-FCH, were investigated: 18F-D4-FCH import, CHKA phosphorylation activity, and efflux of [18 F]-D4-FCH and its phosphorylated product [18F]-D4-FCHP. Effects of hypoxia on [18 F]-D4-FCH uptake were studied in CHKA-overexpressing cell lines of prostate cancer, PC-3, and breast cancer, MDA-MB-231 cells. Mechanisms of radiotracer efflux were assessed by cell uptake and immunofluorescence in vitro, and examined in vivo (N=24). Mathematical modelling methodology was further developed to verify efflux hypothesis using [18 F]-D4-FCH dynamic PET scans from non-small cell lung cancer (NSCLC) patients (N=17). We report a novel finding involving export of phosphorylated[18F]-D4-FCH, [18 F]-D4-FCHP, via HIF-1α-responsive efflux transporters including ABCB4 when HIF-1α level is augmented. This is supported by graphical analysis of human data with a compartmental model (M2T6k+k5) that accounts for efflux. Hypoxia/HIF-1α increases the efflux of phosphorylated radiolabelled choline species, thus supporting consideration of efflux in modelling of radiotracer dynamics.

Journal article

McAteer MA, O'Connor JPB, Koh DM, Leung HY, Doran SJ, Jauregui-Osoro M, Muirhead N, Brew-Graves C, Plummer ER, Sala E, Ng T, Aboagye EO, Higgins GS, Punwani Set al., 2021, Introduction to the National Cancer Imaging Translational Accelerator (NCITA): a UK-wide infrastructure for multicentre clinical translation of cancer imaging biomarkers, British Journal of Cancer, ISSN: 0007-0920

The National Cancer Imaging Translational Accelerator (NCITA) is creating a UK national coordinated infrastructure for accelerated translation of imaging biomarkers for clinical use. Through the development of standardised protocols, data integration tools and ongoing training programmes, NCITA provides a unique scalable infrastructure for imaging biomarker qualification using multicentre clinical studies.

Journal article

Aboagye E, Young JD, Jauregui-Osoro M, Wong W-L, Cooper M, Cook G, Barrington S, Ma MT, Blower Pet al., 2021, An overview of nuclear medicine research in the UK and the landscape for clinical adoption, Nuclear Medicine Communications, Vol: 42, Pages: 1301-1312, ISSN: 0143-3636

Background and objectives Nuclear medicine contributes greatly to the clinical management of patients and experimental medicine. This report aims to (1) outline the current landscape of nuclear medicine research in the UK, including current facilities and recent or ongoing clinical studies and (2) provide information about the available pathways for clinical adoption and NHS funding (commissioning) of radiopharmaceuticals.Methods Evidence was obtained through database searches for UK-based nuclear medicine clinical studies and by conducting a questionnaire-based survey of UK radiopharmaceutical production facilities. A recent history of clinical commissioning, either through recommendations from the National Institute for Health and Care Excellence (NICE) or through NHS specialised services commissioning, was compiled from publicly available documents and policies.Results The collected data highlighted the UK’s active nuclear medicine research community and recent investment in new facilities and upgrades. All commissioning routes favour radiopharmaceuticals that have marketing authorisation and since 2017 there has been a requirement to demonstrate both clinical and cost-effectiveness. Whilst radiopharmaceuticals for molecular radiotherapy are well suited to these commissioning pathways, diagnostic radiotracers have not historically been assessed in this manner.Conclusions We hope that by collating this information we will provide stimulus for future discussion and consensus statements around this topic.

Journal article

Aboagye E, Wang N, Brickute D, Braga M, Barnes C, Lu H, Allott Let al., 2021, Novel non-congeneric derivatives of the choline kinase alpha inhibitor ICL-CCIC-0019, Pharmaceutics, Vol: 13, Pages: 1-17, ISSN: 1999-4923

Choline kinase alpha (CHKA) is a promising target for the development of cancer therapeutics. We have previously reported ICL-CCIC-0019, a potent CHKA inhibitor with high cellular activity but with some unfavorable pharmacological properties. In this work, we present an active analogue of ICL-CCIC-0019 bearing a piperazine handle (CK146) to facilitate further structural elaboration of the pharmacophore and thus improve the biological profile. Two different strategies were evaluated in this study: (1) a prodrug approach whereby selective CHKA inhibition could be achieved through modulating the activity of CK146, via the incorporation of an ε-(Ac) Lys motif, cleavable by elevated levels of histone deacetylase (HDAC) and cathepsin L (CTSL) in tumour cells; (2) a prostate-specific membrane antigen (PSMA) receptor targeted delivery strategy. Prodrug (CK145) and PSMA-targeted (CK147) derivatives were successfully synthesized and evaluated in vitro. While the exploitation of CK146 in those two strategies did not deliver the expected results, important and informative structure-activity relationships were observed and have been reported.

Journal article

Vassileva V, Braga M, Barnes C, Przystal J, Ashek A, Allott L, Brickute D, Abrahams J, Suwan K, Carcaboso AM, Hajitou A, Aboagye EOet al., 2021, Effective detection and monitoring of glioma using [18F]FPIA PET imaging, Biomedicines, Vol: 9, Pages: 1-14, ISSN: 2227-9059

Background: Reprogrammed cellular metabolism is a cancer hallmark. In addition to increased glycolysis, the oxidation of acetate in the citric acid cycle is another common metabolic phenotype. We have recently developed a novel fluorine-18-labelled trimethylacetate-based radiotracer, [18F]fluoro-pivalic acid ([18F]FPIA), for imaging the transcellular flux of short-chain fatty acids, and investigated whether this radiotracer can be used for the detection of glioma growth. Methods: We evaluated the potential of [18F]FPIA PET to monitor tumor growth in orthotopic patient-derived (HSJD-GBM-001) and cell line-derived (U87, LN229) glioma xenografts, and also included [18F]FDG PET for comparison. We assessed proliferation (Ki-67) and the expression of lipid metabolism and transport proteins (CPT1, SLC22A2, SLC22A5, SLC25A20) by immunohistochemistry, along with etomoxir treatment to provide insights into [18F]FPIA uptake. Results: Longitudinal PET imaging showed gradual increase in [18F]FPIA uptake in orthotopic glioma models with disease progression (p < 0.0001), and high tumor-to-brain contrast compared to [18F]FDG (p < 0.0001). [18F]FPIA uptake correlated positively with Ki-67 (p < 0.01), SLC22A5 (p < 0.001) and SLC25A20 (p = 0.001), and negatively with CPT1 (p < 0.01) and SLC22A2 (p < 0.01). Etomoxir reduced [18F]FPIA uptake, which correlated with decreased Ki-67 (p < 0.05). Conclusions: Our findings support the use of [18F]FPIA PET for the detection and longitudinal monitoring of glioma, showing a positive correlation with tumor proliferation, and suggest transcellular flux-mediated radiotracer uptake.

Journal article

Allott L, Chen C, Braga M, Leung SFJ, Wang N, Barnes C, Brickute D, Carroll L, Aboagye EOet al., 2021, Detecting hypoxia in vitro using 18F-pretargeted IEDDA “click” chemistry in live cells, RSC Advances: an international journal to further the chemical sciences, Vol: 11, Pages: 20335-20341, ISSN: 2046-2069

We have exemplified a pretargeted approach to interrogate hypoxia in live cells using radioactive bioorthogonal inverse electron demand Diels–Alder (IEDDA) “click” chemistry. Our novel 18F-tetrazine probe ([18F]FB-Tz) and 2-nitroimidazole-based TCO targeting molecule (8) showed statistically significant (P < 0.0001) uptake in hypoxic cells (ca. 90 %ID per mg) vs. normoxic cells (<10 %ID per mg) in a 60 min incubation of [18F]FB-Tz. This is the first time that an intracellularly targeted small-molecule for IEDDA “click” has been used in conjunction with a radioactive reporter molecule in live cells and may be a useful tool with far-reaching applicability for a variety of applications.

Journal article

Boubnovski Martell M, Chen M, Linton-Reid K, Posma JM, Copley S, Aboagye Eet al., 2021, [pre-print] Development of a Multi-Task Learning V-Net for Pulmonary Lobar Segmentation on Computed Tomography and Application to Diseased Lungs, Publisher: arXiv

Automated lobar segmentation allows regional evaluation of lung disease and is important for diagnosis and therapy planning. Advanced statistical workflows permitting such evaluation is a needed area within respiratory medicine; their adoption remains slow, with poor workflow accuracy. Diseased lung regions often produce high-density zones on CT images, limiting an algorithm's execution to specify damaged lobes due to oblique or lacking fissures. This impact motivated developing an improved machine learning method to segment lung lobes that utilises tracheobronchial tree information to enhance segmentation accuracy through the algorithm's spatial familiarity to define lobar extent more accurately. The method undertakes parallel segmentation of lobes and auxiliary tissues simultaneously by employing multi-task learning (MTL) in conjunction with V-Net-attention, a popular convolutional neural network in the imaging realm. In keeping with the model's adeptness for better generalisation, high performance was retained in an external dataset of patients with four distinct diseases: severe lung cancer, COVID-19 pneumonitis, collapsed lungs and Chronic Obstructive Pulmonary Disease (COPD), even though the training data included none of these cases. The benefit of our external validation test is specifically relevant since our choice includes those patients who have diagnosed lung disease with associated radiological abnormalities. To ensure equal rank is given to all segmentations in the main task we report the following performance (Dice score) on a per-segment basis: normal lungs 0.97, COPD 0.94, lung cancer 0.94, COVID-19 pneumonitis 0.94 and collapsed lung 0.92, all at p<0.05. Even segmenting lobes with large deformations on CT images, the model maintained high accuracy. The approach can be readily adopted in the clinical setting as a robust tool for radiologists.

Working paper

Allott L, Amgheib A, Barnes C, Braga M, Brickute D, Wang N, Fu R, Ghaem-Maghami S, Aboagye EOet al., 2021, Radiolabelling an F-18 biologic via facile IEDDA "click" chemistry on the GE FASTLab (TM) platform, Reaction Chemistry and Engineering, Vol: 6, Pages: 1070-1078, ISSN: 2058-9883

The use of biologics in positron emission tomography (PET) imaging is an important area of radiopharmaceutical development and new automated methods are required to facilitate their production. We report an automated radiosynthesis method to produce a radiolabelled biologic via facile inverse electron demand Diels–Alder (IEDDA) “click” chemistry on a single GE FASTLab™ cassette. We exemplified the method by producing a fluorine-18 radiolabelled interleukin-2 (IL2) radioconjugate from a trans-cyclooctene (TCO) modified IL2 precursor. The radioconjugate was produced using a fully automated radiosynthesis on a single FASTLab™ cassette in a decay-corrected radiochemical yield (RCY, d.c.) of 19.8 ± 2.6% in 110 min (from start of synthesis); the molar activity was 132.3 ± 14.6 GBq μmol−1. The in vitro uptake of [18F]TTCO-IL2 correlated with the differential receptor expression (CD25, CD122, CD132) in PC3, NK-92 and activated human PBMCs. The automated method may be adapted for the radiosynthesis of any TCO-modified protein via IEDDA chemistry.

Journal article

Lu H, Cunnea P, Nixon K, Rinne N, Aboagye EO, Fotopoulou Cet al., 2021, Discovery of a biomarker candidate for surgical stratification in high-grade serous ovarian cancer, British Journal of Cancer, Vol: 124, Pages: 1286-1293, ISSN: 0007-0920

Background: Maximal effort cytoreductive surgery is associated with improved outcomes in advanced high-grade serous ovarian cancer (HGSOC). However, despite complete gross resection (CGR), there is a percentage of patients who will relapse and die early. The aim of this study is to identify potential candidate biomarkers to help personalise surgical radicality.Methods: 136 advanced HGSOC cases who underwent CGR were identified from three public transcriptomic datasets. Candidate prognostic biomarkers were discovered in this cohort by Cox regression analysis, and further validated by targeted RNA-sequencing in HGSOC cases from Imperial College Healthcare NHS Trust (n = 59), and a public dataset. Gene set enrichment analysis was performed to understand the biological significance of the candidate biomarker.Results: We identified ALG5 as a prognostic biomarker for early tumour progression in advanced HGSOC despite CGR (HR = 2.42, 95% CI (1.57–3.75), p < 0.0001). The prognostic value of this new candidate biomarker was additionally confirmed in two independent datasets (HR = 1.60, 95% CI (1.03–2.49), p = 0.0368; HR = 3.08, 95% CI (1.07–8.81), p = 0.0365). Mechanistically, the oxidative phosphorylation was demonstrated as a potential biological pathway of ALG5-high expression in patients with early relapse (p < 0.001).Conclusion: ALG5 has been identified as an independent prognostic biomarker for poor prognosis in advanced HGSOC patients despite CGR. This sets a promising platform for biomarker combinations and further validations towards future personalised surgical care.

Journal article

Brickute D, Beckley A, Allott L, Costa Braga M, Barnes C, Thorley KJ, Aboagye Eet al., 2021, Synthesis and evaluation of 3’-[18F]fluorothymidine-5’-squaryl as a bioisostere of 3’-[18F]fluorothymidine-5’-monophosphate, RSC Advances: an international journal to further the chemical sciences, Vol: 11, Pages: 12423-12433, ISSN: 2046-2069

The squaryl moiety has emerged as an important phosphate bioisostere with reportedly greater cell permeability. It has been used in the synthesis of several therapeutic drug molecules including nucleoside and nucleotide analogues but is yet to be evaluated in the context of positron emission tomography (PET) imaging. We have designed, synthesised and evaluated 3′-[18F]fluorothymidine-5′-squaryl ([18F]SqFLT) as a bioisostere to 3′-[18F]fluorothymidine-5′-monophosphate ([18F]FLTMP) for imaging thymidylate kinase (TMPK) activity. The overall radiochemical yield (RCY) was 6.7 ± 2.5% and radiochemical purity (RCP) was >90%. Biological evaluation in vitro showed low tracer uptake (<0.3% ID mg−1) but significantly discriminated between wildtype HCT116 and CRISPR/Cas9 generated TMPK knockdown HCT116shTMPK−. Evaluation of [18F]SqFLT in HCT116 and HCT116shTMPK− xenograft mouse models showed statistically significant differences in tumour uptake, but lacked an effective tissue retention mechanism, making the radiotracer in its current form unsuitable for PET imaging of proliferation.

Journal article

Hu Z, Cunnea P, Zhong Z, Lu H, Osagie OI, Campo L, Artibani M, Nixon K, Ploski J, Santana Gonzalez L, Alsaadi A, Wietek N, Damato S, Dhar S, Blagden SP, Yau C, Hester J, Albukhari A, Aboagye EO, Fotopoulou C, Ahmed Aet al., 2021, The Oxford Classic links epithelial-to-mesenchymal transition to immunosuppression in poor prognosis ovarian cancers, Clinical Cancer Research, Vol: 27, Pages: 1570-1579, ISSN: 1078-0432

Purpose: Using RNA sequencing, we recently developed the 52-gene–based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier.Experimental Design: We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples (n = 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy. We performed data mining of published expression profiles of SOCs and validated the classifier results on tissue arrays comprising 137 SOCs.Results: We found evidence of profound nongenetic heterogeneity in SOCs. Approximately 20% of SOCs were classified as epithelial-to-mesenchymal transition–high (EMT-high) tumors, which were associated with poor survival. This was independent of established prognostic factors, such as tumor stage, tumor grade, and residual disease after surgery (HR, 3.3; P = 0.02). Mining expression data of 593 patients revealed a significant association between the EMT scores of tumors and the estimated fraction of alternatively activated macrophages (M2; P < 0.0001), suggesting a mechanistic link between immunosuppression and poor prognosis in EMT-high tumors.Conclusions: The OxC-defined EMT-high SOCs carry particularly poor prognosis independent of established clinical parameters. These tumors are associated with high frequency of immunosuppressive macrophages, suggesting a potential therapeutic target to improve clinical outcome.

Journal article

Kenny LM, Gopalakrishnan GS, Barwick TD, Vaja V, McDevitt SH, Punjani R, Patel NH, Ramakrishnan R, Patel NR, Johnston S, Mansi J, Cook GJ, Gilbert FJ, Aigbirhio FI, Hiscock D, Aboagye EOet al., 2021, Herpet study- PET imaging of HER2 expression in breast cancer using the novel Affibody tracer [18F]GE-226, a first in patient study, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Natoli M, Gallon J, Lu H, Amgheib A, Pinato D, Mauri F, Marafioti T, Akraca A, Ullmo I, Ip J, Aboagye E, Brown R, Karadimitris A, Ghaem-Maghami Set al., 2021, Transcriptional analysis of multiple ovarian cancer cohorts reveals prognostic and immunomodulatory consequences of ERV expression, Journal for ImmunoTherapy of Cancer, Vol: 9, ISSN: 2051-1426

Background Endogenous retroviruses (ERVs) play a role in a variety of biological processes, including embryogenesis and cancer. DNA methyltransferase inhibitors (DNMTi)-induced ERV expression triggers interferon responses in ovarian cancer cells via the viral sensing machinery. Baseline expression of ERVs also occurs in cancer cells, though this process is poorly understood and previously unexplored in epithelial ovarian cancer (EOC). Here, the prognostic and immunomodulatory consequences of baseline ERV expression was assessed in EOC.Methods ERV expression was assessed using EOC transcriptional data from The Cancer Genome Atlas (TCGA) and from an independent cohort (Hammersmith Hospital, HH), as well as from untreated or DNMTi-treated EOC cell lines. Least absolute shrinkage and selection operator (LASSO) logistic regression defined an ERV expression score to predict patient prognosis. Immunohistochemistry (IHC) was conducted on the HH cohort. Combination of DNMTi treatment with γδ T cells was tested in vitro, using EOC cell lines and patient-derived tumor cells.Results ERV expression was found to define clinically relevant subsets of EOC patients. An ERV prognostic score was successfully generated in TCGA and validated in the independent cohort. In EOC patients from this cohort, a high ERV score was associated with better survival (log-rank p=0.0009) and correlated with infiltration of CD8+PD1+T cells (r=0.46, p=0.0001). In the TCGA dataset, a higher ERV score was found in BRCA1/2 mutant tumors, compared to wild type (p=0.015), while a lower ERV score was found in CCNE1 amplified tumors, compared to wild type (p=0.019). In vitro, baseline ERV expression dictates the level of ERV induction in response to DNMTi. Manipulation of an ERV expression threshold by DNMTi resulted in improved EOC cell killing by cytotoxic immune cells.Conclusions These findings uncover the potential for baseline ERV expression to robustly inform EOC patient prognosis, influence

Journal article

Santhirasekaram A, Pinto K, Winkler M, Aboagye E, Glocker B, Rockall Aet al., 2021, Multi-scale Hybrid Transformer Networks: Application to Prostate Disease Classification, Pages: 12-21, ISSN: 0302-9743

Automated disease classification could significantly improve the accuracy of prostate cancer diagnosis on MRI, which is a difficult task even for trained experts. Convolutional neural networks (CNNs) have shown some promising results for disease classification on multi-parametric MRI. However, CNNs struggle to extract robust global features about the anatomy which may provide important contextual information for further improving classification accuracy. Here, we propose a novel multi-scale hybrid CNN/transformer architecture with the ability of better contextualising local features at different scales. In our application, we found this to significantly improve performance compared to using CNNs. Classification accuracy is even further improved with a stacked ensemble yielding promising results for binary classification of prostate lesions into clinically significant or non-significant.

Conference paper

Arshad MA, Gitau S, Tam H, Park W-HE, Patel NH, Rockall A, Aboagye EO, Bharwani N, Barwick TDet al., 2020, Optimal method for metabolic tumour volume assessment of cervical cancers with inter-observer agreement on [18F]-fluoro-deoxy-glucose positron emission tomography with computed tomography, European Journal of Nuclear Medicine and Molecular Imaging, Pages: 1-15, ISSN: 0340-6997

PurposeCervical cancer metabolic tumour volume (MTV) derived from [18F]-FDG PET/CT has a role in prognostication and therapy planning. There is no standard method of outlining MTV on [18F]-FDG PET/CT. The aim of this study was to assess the optimal method to outline primary cervical tumours on [18F]-FDG PET/CT using MRI-derived tumour volumes as the reference standard.Methods81 consecutive cervical cancer patients with pre-treatment staging MRI and [18F]-FDG PET/CT imaging were included. MRI volumes were compared with different PET segmentation methods. Method 1 measured MTVs at different SUVmax thresholds ranging from 20 to 60% (MTV20-MTV60) with bladder masking and manual adjustment when required. Method 2 created an isocontour around the tumour prior to different SUVmax thresholds being applied. Method 3 used an automated gradient method. Inter-observer agreement of MTV, following manual adjustment when required, was recorded.ResultsFor method 1, the MTV25 and MTV30 were closest to the MRI volumes for both readers (mean percentage change from MRI volume of 2.9% and 13.4% for MTV25 and − 13.1% and − 2.0% for MTV30 for readers 1 and 2). 70% of lesions required manual adjustment at MTV25 compared with 45% at MTV30. There was excellent inter-observer agreement between MTV30 to MTV60 (ICC ranged from 0.898–0.976 with narrow 95% confidence intervals (CIs)) and moderate agreement at lower thresholds (ICC estimates of 0.534 and 0.617, respectively for the MTV20 and MTV25 with wide 95% CIs). Bladder masking was performed in 86% of cases overall. For method 2, excellent correlation was demonstrated at MTV25 and MTV30 (mean % change from MRI volume of −3.9% and − 8.6% for MTV25 and − 16.9% and 19% for MTV30 for readers 1 and 2, respectively). This method also demonstrated excellent ICC across all thresholds with no manual adjustment. Method 3 demonstrated excellent ICC of 0.96 (95% CI 0.94–0.97) but had a

Journal article

Ordonez AA, Abhishek S, Singh AK, Klunk MH, Azad BB, Aboagye EO, Carroll L, Jain SKet al., 2020, Caspase-based PET for evaluating pro-apoptotic treatments in a tuberculosis mouse model, Molecular Imaging and Biology, Vol: 22, Pages: 1489-1494, ISSN: 1095-0397

PurposeDespite recent advances in antimicrobial treatments, tuberculosis (TB) remains a major global health threat. Mycobacterium tuberculosis proliferates in macrophages, preventing apoptosis by inducing anti-apoptotic proteins leading to necrosis of the infected cells. Necrosis then leads to increased tissue destruction, reducing the penetration of antimicrobials and immune cells to the areas where they are needed most. Pro-apoptotic drugs could be used as host-directed therapies in TB to improve antimicrobial treatments and patient outcomes.ProcedureWe evaluated [18F]-ICMT-11, a caspase-3/7-specific positron emission tomography (PET) radiotracer, in macrophage cell cultures and in an animal model of pulmonary TB that closely resembles human disease.ResultsCells infected with M. tuberculosis and treated with cisplatin accumulated [18F]-ICMT-11 at significantly higher levels compared with that of controls, which correlated with levels of caspase-3/7 activity. Infected mice treated with cisplatin with increased caspase-3/7 activity also had a higher [18F]-ICMT-11 PET signal compared with that of untreated infected animals.Conclusions[18F]-ICMT-11 PET could be used as a noninvasive approach to measure intralesional pro-apoptotic responses in situ in pulmonary TB models and support the development of pro-apoptotic host-directed therapies for TB.

Journal article

Aboagye E, Sharma R, Inglese M, Dubash S, Lu H, Pinato D, Patel N, Chung A, Sanghera C, Tait A, Mauri F, Crum W, Barwick Tet al., 2020, Monitoring response to transarterial chemoembolization in hepatocellular carcinoma using 18F-Fluorothymidine Positron Emission Tomography, The Journal of Nuclear Medicine, Vol: 61, Pages: 1743-1748, ISSN: 0161-5505

Accurate disease monitoring is essential following transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) due to potential for profound adverse event and large variation in survival outcome. Post-treatment changes on conventional imaging can confound determination of residual/recurrent disease, magnifying the clinical challenge. Based on increased expression of thymidylate synthase (TYMS), thymidine kinase-1 (TK-1) and SLC29A1 (Equilibrative nucleoside transporter 1, ENT1) in HCC compared with liver tissue, we conducted a proof of concept study evaluating the efficacy of 18F-fluorothymidine (18F-FLT)-PET to assess response to TACE. As previous PET studies in HCC have been hampered by high background liver signal, we investigated if a temporal-intensity voxel-clustering (“Kinetic Spatial Filtering”) (KSF) improved lesion detection. Methods: A tissue microarray (TMA) was built from 36 HCC samples and matched surrounding cirrhotic tissue and was stained for thymidine kinase-1 (TK-1). A prospective study was conducted; eighteen patients with a diagnosis of HCC by American Association for the Study of Liver Diseases criteria (AALSD) who were eligible to treatment with TACE were enrolled. Patients underwent baseline conventional imaging and dynamic 18F-FLT-PET/KSF followed by TACE. Repeat imaging was performed 6-8 weeks post TACE. PET parameters were compared with modified-Response Evaluation in Solid Tumours (mRECIST) enhancement-based criteria. Results: Cancer Genome Atlas analysis revealed increased RNA expression of TYMS, TK-1 and SLC29A1 in HCC. TK-1 protein expression was significantly higher in HCC (p<0.05). The sensitivity of 18F-FLT-PET for baseline HCC detection was 73% (SUVmax of 9.7 ± 3.0; tumour to liver ratio of 1.2 ± 0.3). Application of KSF did not improve lesion detection. Lesion response following TACE by mRECIST criteria was 58% (14 patients with 24 lesions). A 30% reduction in mean 18F-FLT-PET uptake was o

Journal article

Ferris T, Carroll L, Jenner S, Aboagye EOet al., 2020, Use of radioiodine in nuclear medicine-A brief overview, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, Vol: 64, Pages: 92-108, ISSN: 0362-4803

Journal article

Dubash S, Keat N, Kozlowski K, Barnes C, Allott L, Brickute D, Hill S, Huiban M, Barwick T, Kenny L, Aboagye Eet al., 2020, Clinical translation of 18F-fluoropivalate – a PET tracer for imaging short-chain fatty acid metabolism: safety, biodistribution, and dosimetry in fed and fasted healthy volunteers, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 47, Pages: 2549-2561, ISSN: 1619-7070

BackgroundFatty acids derived de novo or taken up from the extracellular space are an essential source of nutrient for cell growth and proliferation. Radiopharmaceuticals including 11C-acetate, and 18F-FAC (2-18F-fluoroacetate), have previously been used to study short-chain fatty acid (SCFA) metabolism. We developed 18F-fluoropivalate (18F-FPIA; 3-18F-fluoro-2,2-dimethylpropionic acid) bearing a gem-dimethyl substituent to assert metabolic stability for studying SCFA metabolism. We report the safety, biodistribution, and internal radiation dosimetry profile of 18F-FPIA in 24 healthy volunteers and the effect of dietary conditions.Materials and methodsHealthy volunteer male and female subjects were enrolled (n = 24), and grouped into 12 fed and 12 fasted. Non-esterified fatty acids (NEFA) and carnitine blood measurements were assessed. Subjects received 159.48 MBq (range, 47.31–164.66 MBq) of 18F-FPIA. Radiochemical purity was > 99%. Safety data were obtained during and 24 h after radiotracer administration. Subjects underwent detailed multiple whole-body PET/CT scanning with sampling of venous bloods for radioactivity and radioactive metabolite quantification. Regions of interest were defined to derive individual and mean organ residence times; effective dose was calculated using OLINDA 1.1.ResultsAll subjects tolerated 18F-FPIA with no adverse events. Over 90% of radiotracer was present in plasma at 60 min post-injection. The organs receiving highest absorbed dose (in mGy/MBq) were the liver (0.070 ± 0.023), kidneys (0.043 ± 0.013), gallbladder wall (0.026 ± 0.003), and urinary bladder (0.021 ± 0.004); otherwise there was low tissue uptake. The calculated effective dose using mean organ residence times over all 24 subjects was 0.0154 mSv/MBq (SD ± 0.0010). No differences in biodistribution or dosimetry were seen in fed and fasted subjects

Journal article

Cesarec S, Robson JA, Carroll LS, Aboagye EO, Spivey ACet al., 2020, Direct incorporation of [18F] into Aliphatic Systems: a promising Mn-catalysed labelling technique for PET imaging, Current Radiopharmaceuticals, Vol: 13, ISSN: 1874-4710

BACKGROUND: One of the challenges in positron emission tomography (PET) is labellingcomplex aliphatic molecules. OBJECTIVE: This study aimed to develop a method of metal-catalysed radiofluorination that is site-selectiveand works in moderate to good yields under facile conditions. METHODS: Herein, we report on the optimisation of an aliphatic C-H to C-18F bond transformationcatalysed by a Mn(porphyrin) complex. RESULTS: The successful oxidation of 11 aliphatic molecules, including progesterone, is reported.Radiochemical Incorporations (RCIs) up to 69% were achieved within 60 min without the need forpre-activation or special equipment. CONCLUSION: The method features mild conditions (60 °C) and promises to constitute a valuable approachto labelling of biomolecules and drug substances.

Journal article

Dubash S, Inglese M, Mauri F, Kozlowski K, Trivedi P, Arshad M, Challapalli A, Barwick T, Al-Nahhas A, Stanbridge R, Lewanski C, Berry M, Bowen F, Aboagye EOet al., 2020, Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [F-18]fluoromethyl-(1,2-H-2(4))-choline, Theranostics, Vol: 10, Pages: 8677-8690, ISSN: 1838-7640

Purpose: The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous. Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy. However, non-invasive methods to assess this phenomenon in patients are limited. We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [18F]fluoromethyl-(1,2-2H4) choline ([18F]D4-FCH) and positron emission tomography/computed tomography (PET/CT).Experimental design: [18F]D4-FCH (300.5±72.9MBq [147.60-363.6MBq]) was administered intravenously to 17 newly diagnosed NSCLC patients. PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants. Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [18F]fluorodeoxyglucose ([18F]FDG) scans.Results: Oxidation of [18F]D4-FCH to [18F]D4-fluorobetaine was suppressed (48.58±0.31% parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer. Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed. [18F]D4-FCH-derived uptake (SUV60max) in index primary lesions (n=17) ranged between 2.87-10.13; lower than that of [18F]FDG PET [6.89-22.64]. Mathematical modelling demonstrated net irreversible uptake of [18F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression.Conclusions: [18F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy.

Journal article

Allott L, Aboagye EO, 2020, Chemistry considerations for the clinical translation of oncology PET radiopharmaceuticals, Molecular Pharmaceutics, Vol: 17, Pages: 2245-2259, ISSN: 1543-8384

Positron emission tomography (PET) has proven to be an invaluable tool in the staging and management of disease in oncology; however, [18F]fluorodeoxyglucose ([18F]FDG) remains the most widely used PET radiopharmaceutical despite the large financial investment in novel radiotracer development. We report our perspective and experience of translating radiopharmaceuticals into clinical studies, discussing the PET development pipeline from a chemistry perspective. We hope that, by identifying potential points of attrition along the pipeline and suggesting solutions to these problems, we may help others take their preclinical radiotracers into human studies. This review focuses primarily on the development of fluorine-18 radiopharmaceuticals, although the broader field of radiometal chemistry is considered where the translation journey is similar.

Journal article

Braga M, Kaliszczak M, Carroll L, Schug ZT, Heinzmann K, Baxan N, Benito A, Valbuena GN, Stribbling S, Beckley A, Mackay G, Mauri F, Latigo J, Barnes C, Keun H, Gottlieb E, Aboagye EOet al., 2020, Tracing nutrient flux following monocarboxylate transporter-1 inhibition with AZD3965., Cancers (Basel), Vol: 12, ISSN: 2072-6694

The monocarboxylate transporter 1 (MCT1) is a key element in tumor cell metabolism and inhibition of MCT1 with AZD3965 is undergoing clinical trials. We aimed to investigate nutrient fluxes associated with MCT1 inhibition by AZD3965 to identify possible biomarkers of drug action. We synthesized an 18F-labeled lactate analogue, [18F]-S-fluorolactate ([18F]-S-FL), that was used alongside [18F]fluorodeoxyglucose ([18F]FDG), and 13C-labeled glucose and lactate, to investigate the modulation of metabolism with AZD3965 in diffuse large B-cell lymphoma models in NOD/SCID mice. Comparative analysis of glucose and lactate-based probes showed a preference for glycolytic metabolism in vitro, whereas in vivo, both glucose and lactate were used as metabolic fuel. While intratumoral L-[1-13C]lactate and [18F]-S-FL were unchanged or lower at early (5 or 30 min) timepoints, these variables were higher compared to vehicle controls at 4 h following treatment with AZD3965, which indicates that inhibition of MCT1-mediated lactate import is reversed over time. Nonetheless, AZD3965 treatment impaired DLBCL tumor growth in mice. This was hypothesized to be a consequence of metabolic strain, as AZD3965 treatment showed a reduction in glycolytic intermediates and inhibition of the TCA cycle likely due to downregulated PDH activity. Glucose ([18F]FDG and D-[13C6]glucose) and lactate-based probes ([18F]-S-FL and L-[1-13C]lactate) can be successfully used as biomarkers for AZD3965 treatment.

Journal article

Allott L, Brickute D, Chen C, Barnes C, Wang N, Aboagye Eet al., 2020, Development of a fluorine-18 radiolabelled fluorescent chalcone: evaluated for detecting glycogen", EJNMMI Radiopharmacy and Chemistry, Vol: 5, Pages: 1-17, ISSN: 2365-421X

Background: Glycogen is a multibranched polysaccharide of glucose produced by cells to store energy and plays a key role in cancer. A previously reported fluorescent probe (CDg4) was shown to selectively bind glycogen in mouse embryonic stem cells, however the molecule was not evaluated in cancer cells. We report the synthesis and biological evaluation of a dual-modality imaging probe based on CDg4, for positron emission tomography (PET) and fluorescence microscopy. Results: A fluorine-18 radiolabelled derivative of CDg4, ([18F]5) for in vivo quantification of total glycogen levels in cancer cells was developed and synthesised in 170 min with a non-decay corrected radiochemical yield (RCY n.d.c) of 5.1 ± 0.9 % (n = 4) in >98% radiochemical purity. Compound 5 and [18F]5 were evaluated in vitro for their potential to bind glycogen, but only 5 showed accumulation by fluorescence microscopy. The accumulation of 5 was determined to be specific as fluorescent signal diminished upon the digestion of carbohydrate polymers with α-amylase. PET imaging in non-tumour bearing mice highlighted rapid hepato-biliary-intestinal elimination of [18F]5 and almost complete metabolic degradation after 60 min in the liver, plasma and urine, confirmed by radioactive metabolite analysis.Conclusions: Fluorescent compound 5 selectively accumulated in glycogen containing cancer cells, identified by fluorescence microscopy; however, rapid in vivo metabolic degradation precludes further investigation of [18F]5 as a PET radiopharmaceutical.

Journal article

Tarkin JM, Wall C, Gopalan D, Aloj L, Manavaki R, Fryer TD, Aboagye EO, Bennett MR, Peters JE, Rudd JHF, Mason JCet al., 2020, Novel approach to imaging active takayasu arteritis using somatostatin receptor positron emission tomography/magnetic resonance imaging., Circulation: Cardiovascular Imaging, Vol: 13, Pages: 1-3, ISSN: 1941-9651

Although 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is an important diagnostic test for Takayasu arteritis (TAK),118F-FDG lacks inflammatory cell selectivity and cannot accurately distinguish arteritis from metabolically active vascular remodeling.2 This observation has led to the search for more sensitive and specific PET tracers for TAK. Macrophage activation antigen SST2 (somatostatin receptor subtype-2) PET represents a potential alternative imaging biomarker for defining disease activity in TAK, as macrophages are a major feature of the inflammatory infiltrate. We aimed to determine the ability of SST2 PET/magnetic resonance imaging (MRI) to detect arteritis in 2 patients with clinically active TAK.

Journal article

Sharma R, Valls PO, Inglese M, Dubash S, Chen M, Gabra H, Montes A, Challapalli A, Arshad M, Tharakan G, Chambers E, Cole T, Lozano-Kuehne JP, Barwick TD, Aboagye EOet al., 2020, [18F]Fluciclatide PET as a biomarker of response to combination therapy of pazopanib and paclitaxel in platinum-resistant/refractory ovarian cancer, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 47, Pages: 1239-1251, ISSN: 0340-6997

BACKGROUND: Angiogenesis is a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum-resistant/refractory ovarian cancer. Integrins αvβ3 and αvβ5 are both upregulated in tumor-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvβ3/5, and was used to assess the anti-angiogenic effect of pazopanib. PATIENTS AND METHODS: We conducted an open-label, phase Ib study in patients with platinum-resistant/refractory ovarian cancer. Patients received 1 week of single-agent pazopanib (800 mg daily) followed by combination therapy with weekly paclitaxel (80 mg/m2). Following completion of 18 weeks of combination therapy, patients continued with single-agent pazopanib until disease progression. Dynamic [18F]fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities, and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. RESULTS: Fourteen patients were included in the intention-to-treat analysis. Complete and partial responses were seen in seven patients (54%). Median progression-free survival (PFS) was 10.63 months, and overall survival (OS) was 18.5 months. Baseline [18F]fluciclatide uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and fibroblast growth factor (FGF) were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modeling of PET data indicated a reduction in K1 and Ki following pazopanib indicating reduced radioligand delivery and retention. CONCLUSIONS: Combination therapy followed by maintenance pazopanib is effective and tolerable in platinum-resistant/refractory ovarian cancer. [18F]Fluciclatide-PET uptake parameters predict clinical outcome with pazopanib therapy indicating an anti

Journal article

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