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

351 results found

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

<jats:sec><jats:title>Background:</jats:title><jats:p>One of the challenges in positron emission tomography (PET) is labelling complex aliphaticmolecules.</jats:p></jats:sec><jats:sec><jats:title>Objective:</jats:title><jats:p>To develop a method of metal-catalysed radiofluorination that is site-selective and works in moderate to goodyields under facile conditions.</jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> We report here on the optimisation of an aliphatic C-H to C-18F bond transformation catalysed by aMn(porphyrin) complex.</jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> The successful oxidation of 11 aliphatic molecules including progesterone are reported. RadiochemicalIncorporations (RCIs) up to 69% were achieved within 60 min without the need for pre-activation or specialist equipment.</jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p>The method features mild conditions (60 °C) and promises to constitute a valuable approach to labelling ofbiomolecules and drug substances.</jats:p></jats:sec>

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

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, 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

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

Allott L, Dubash S, Aboagye EO, 2020, [18F]FET-βAG-TOCA: the design, evaluation and clinical translation of a fluorinated octreotide, Cancers, Vol: 12, ISSN: 2072-6694

The success of Lutathera™ ([177Lu]Lu-DOTA-TATE) in the NETTER-1 clinical trial as a peptide receptor radionuclide therapy (PRRT) for somatostatin receptor expressing (SSTR) neuroendocrine tumours (NET) is likely to increase the demand for patient stratification by positron emission tomography (PET). The current gold standard of gallium-68 radiolabelled somatostatin analogues (e.g., [68Ga]Ga-DOTA-TATE) works effectively, but access is constrained by the limited availability and scalability of gallium-68 radiopharmaceutical production. The aim of this review is three-fold: firstly, we discuss the peptide library design, biological evaluation and clinical translation of [18F]fluoroethyltriazole-βAG-TOCA ([18F]FET-βAG-TOCA), our fluorine-18 radiolabelled octreotide; secondly, to exemplify the potential of the 2-[18F]fluoroethylazide prosthetic group and copper-catalysed azide-alkyne cycloaddition (CuAAC) chemistry in accessing good manufacturing practice (GMP) compatible radiopharmaceuticals; thirdly, we aim to illustrate a framework for the translation of similarly radiolabelled peptides, in which in vivo pharmacokinetics drives candidate selection, supported by robust radiochemistry methodology and a route to GMP production. It is hoped that this review will continue to inspire the development and translation of fluorine-18 radiolabelled peptides into clinical studies for the benefit of patients.

Journal article

Avesani G, Arshad M, Lu H, Fotopoulou C, Cannone F, Melotti R, Aboagye E, Rockall Aet al., 2020, Radiological assessment of Peritoneal Cancer Index on preoperative CT in ovarian cancer is related to surgical outcome and survival, RADIOLOGIA MEDICA, Vol: 125, Pages: 770-776, ISSN: 0033-8362

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, Pages: 1-6, 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

Sarpaki S, Cortezon-Tamarit F, de Aguiar SRMM, Exner RM, Divall D, Arrowsmith RL, Ge H, Palomares FJ, Carroll L, Calatayud DG, Paisey SJ, Aboagye EO, Pascu SIet al., 2020, Radio- and nano-chemistry of aqueous Ga(iii) ions anchored onto graphene oxide-modified complexes, Nanoscale, Vol: 12, Pages: 6603-6608, ISSN: 2040-3364

The gallium-68 radiolabelling of new functional graphene oxide composites is reported herein along with kinetic stability investigations of the radio-nanohybrids under different environments and insights into their surface characteristics by SEM and XPS. The present work highlights the potential of graphene oxides as nanocarriers for small molecules such as bis(thiosemicarbazonato) complexes to act as multifunctional platforms for rapid and effective radioimaging agent incorporation.

Journal article

Barnes EME, Xu Y, Benito A, Herendi L, Siskos AP, Aboagye EO, Keun H, Nijhuis Aet al., 2020, Lactic acidosis induces resistance to the pan-Akt inhibitor uprosertib in colon cancer cells, British Journal of Cancer, Vol: 122, Pages: 1298-1308, ISSN: 0007-0920

BackgroundAkt signalling regulates glycolysis and drives the Warburg effect in cancer, thus decreased glucose utilisation is a pharmacodynamic marker of Akt inhibition. However, cancer cells can utilise alternative nutrients to glucose for energy such as lactate, which is often elevated in tumours together with increased acidity. We therefore hypothesised that lactic acidosis may confer resistance to Akt inhibition.MethodsThe effect of the pan-Akt inhibitor uprosertib (GSK2141795), on HCT116 and LS174T colon cancer cells was evaluated in the presence and absence of lactic acid in vitro. Expression of downstream Akt signalling proteins was determined using a phosphokinase array and immunoblotting. Metabolism was assessed using 1H nuclear magnetic resonance spectroscopy, stable isotope labelling and gas chromatography-mass spectrometry.ResultsLactic acid-induced resistance to uprosertib was characterised by increased cell survival and reduced apoptosis. Uprosertib treatment reduced Akt signalling and glucose uptake irrespective of lactic acid supplementation. However, incorporation of lactate carbon and enhanced respiration was maintained in the presence of uprosertib and lactic acid. Inhibiting lactate transport or oxidative phosphorylation was sufficient to potentiate apoptosis in the presence of uprosertib.ConclusionsLactic acidosis confers resistance to uprosertib, which can be reversed by inhibiting lactate transport or oxidative metabolism.

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, 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

Tarkin J, Wall C, Gopalan D, Aloi L, Aboagye E, Bennett MR, Peters J, Rudd JHF, Mason Jet al., A novel approach to imaging active Takayasu arteritis using somatostatin receptor PET/MRI ligands, Circulation: Cardiovascular Imaging, ISSN: 1941-9651

Journal article

Glaser M, Rajkumar V, Diocou S, Gendron T, Yan R, Sin PKB, Sander K, Carroll L, Pedley RB, Aboagye EO, Witney TH, Arstad Eet al., 2019, One-pot radiosynthesis and biological evaluation of a caspase-3 selective 5-[(123,)(125) I]iodo-1,2,3-triazole derived satin SPECT tracer, Scientific Reports, Vol: 9, ISSN: 2045-2322

Induction of apoptosis is often necessary for successful cancer therapy, and the non-invasive monitoring of apoptosis post-therapy could assist in clinical decision making. Isatins are a class of compounds that target activated caspase-3 during apoptosis. Here we report the synthesis of the 5-iodo-1,2,3-triazole (FITI) analog of the PET tracer [18F]ICMT11 as a candidate tracer for imaging of apoptosis with SPECT, as well as PET. Labelling with radioiodine (123,125I) was achieved in 55 ± 12% radiochemical yield through a chelator-accelerated one-pot cycloaddition reaction mediated by copper(I) catalysis. The caspase-3 binding affinity and selectivity of FITI compares favourably to that of [18F]ICMT11 (Ki = 6.1 ± 0.9 nM and 12.4 ± 4.7 nM, respectively). In biodistribution studies, etoposide-induced cell death in a SW1222 xenograft model resulted in a 2-fold increase in tumour uptake of the tracer. However, the tumour uptake was too low to allow in vivo imaging of apoptosis with SPECT.

Journal article

Inglese M, Katherine L O, Lesley H, Tara D B, Eric O A, Adam D W, Matthew G-Set al., 2019, Reliability of dynamic contrast enhanced magnetic resonance imaging data in primary brain tumours: a comparison of Tofts and shutter speed models, Neuroradiology, Vol: 61, Pages: 1375-1386, ISSN: 0028-3940

PurposeTo investigate the robustness of pharmacokinetic modelling of DCE-MRI brain tumourdata and to ascertain reliable perfusion parameters through a model selection processand a stability test.MethodsDCE-MRI data of 14 patients with primary brain tumours were analysed using the Toftsmodel (TM), the extended Tofts model (ETM), the shutter speed model (SSM) and theextended shutter speed model (ESSM). A no-effect model (NEM) was implemented toassess overfitting of data by the other models.For each lesion, the Akaike Information Criteria (AIC) was used to build a 3D modelselection map. The variability of each pharmacokinetic parameter extracted from thismap was assessed with a noise propagation procedure, resulting in voxel-wisedistributions of the coefficient of variation (CV).ResultsThe model selection map over all patients showed NEM had the best fit in 35.5% ofvoxels, followed by ETM (32%), TM (28.2%), SSM (4.3%) and ESSM (<0.1%). Inanalysing the reliability of Ktrans, when considering regions with a CV<20%, ≈25% ofvoxels were found to be stable across all patients. The remaining 75% of voxels wereconsidered unreliable.ConclusionsThe majority of studies quantifying DCE-MRI data in brain tumours only consider asingle model and whole-tumour statistics for the output parameters. Appropriate modelselection, considering tissue biology and its effects on blood brain barrier permeabilityand exchange conditions, together with an analysis on the reliability and stability of thecalculated parameters, is critical in processing robust brain tumour DCE-MRI data.

Journal article

Sharma R, Wang WM, Yusuf S, Evans J, Ramaswami R, Wernig F, Frilling A, Mauri F, Al-Nahhas A, Aboagye EO, Barwick TDet al., 2019, 68Ga-DOTATATE PET/CT parameters predict response to peptide receptor radionuclide therapy in neuroendocrine tumours, Radiotherapy and Oncology, Vol: 141, Pages: 108-115, ISSN: 0167-8140

PURPOSE: [177Lu]DOTATATE prolongs progression free survival (PFS) in metastatic neuroendocrine tumours (NETs). However, objective response rate is low. This, coupled with long duration of therapy and expense suggest need for better selection. We aim to assess whether baseline [68Ga]DOTATATE-PET/CT parameters, and whether response assessment by PET accurately predicts clinical outcome to [177Lu]DOTATATE. EXPERIMENTAL DESIGN: Retrospective study of patients receiving [177Lu]DOTATATE was conducted. Patients were followed 3-monthly until disease progression. Four [68Ga]DOTATATE-PET parameters (single lesion SUVmax, tumour to spleen and liver SUV ratios, and SUVmax-av using up to five target lesions in multiple organ sites) were determined at baseline and follow-up. The association between these PET parameters either at baseline, or any changes following treatment, and PET response criteria (PERCIST and modified PERCIST) to predict PFS were determined. Patients were followed 3-monthly until disease progression. Response was determined using RECIST 1.1. Baseline SSTR2 expression was assessed and compared with PET parameters. RESULTS: 55 patients with metastatic NETs were identified predominantly small bowel (N = 18) and pancreatic (N = 8) in origin. 16 were low grade, 15 intermediate and 3 high grade. Response to PRRT (N = 47): partial response (PR) 28%, stable disease (SD) 60% progressive disease (PD) 13%. Response to PRRT predicted PFS: PR 71.8 months (95%CI: not achieved), SD 29.1 months (95%CI: 15.2-43.1), and PD 9.7 months (95%CI: 0-21.02). Baseline, single lesion SUVmax predicted both response and PFS with SUV cut-off of 13.0 giving high sensitivity and specificity. Tumoural SUVmax correlated with SSTR2 expression, Spearman's rho - 0.69, p < 0.01. CONCLUSIONS: Baseline single lesion SUVmax and SUVmax-av predicts response to [177Lu]DOTATATE. Objective response following PRRT defines a subset of patients with markedly improved PFSBaseline SUVmax 13.0 defines a thre

Journal article

Allott L, Barnes C, Brickute D, Leung SFJ, Aboagye EOet al., 2019, Solid-supported cyanoborohydride cartridges for automation of reductive amination radiochemistry, Reaction Chemistry and Engineering, Vol: 4, Pages: 1748-1751, ISSN: 2058-9883

A solid-supported cyanoborohydride cartridge was designed to facilitate the automated production of positron emission tomography (PET) radiotracers synthesised via reductive amination chemistry. Two compounds, N-(4-fluorobenzyl)-2-(2-nitro-1H-imidazol-1-yl)ethan-1-amine ([18F]2) and 1,3,4,6-tetra-O-acetyl-2-(4-fluorobenzylamine)-2-deoxy-β-D-glucopyranose ([18F]4) were radiosynthesised efficiently using a GE FASTlab™ platform, obtained in >98% RCP in a total synthesis time of 75 min (from the start of synthesis) with RCY (non-decay corrected) of 7.5 ± 2.5% and 6.0 ± 1.1%, respectively. The cartridge method provides a convenient alternative to conventional powdered reducing agents typically used in reductive amination radiochemistry.

Journal article

Sharma R, Wang W, Yusuf S, Evans J, Ramaswami R, Wernig F, Frilling A, Mauri F, Al-Nahaas A, Aboagye EO, Barwick TDet al., 2019, [Ga-68]-DOTATATE PET/CT parameters predict response to peptide receptor radionuclide therapy in neuroendocrine tumours, 32nd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S640-S640, ISSN: 1619-7070

Conference paper

Sharma R, Valls PO, Inglese M, Dubash S, Chen M, Gabra H, Montes A, Challapalli A, Arshad M, Thakaran G, Chambers E, Cole T, Lozano-Kuehne J, Barwick TD, Aboagye EOet al., 2019, [F-18]fluciclatide Pet As A Biomarker Of Response To Combination Therapy Of Pazopanib And Paclitaxel In Platinum-resistant/refractory Ovarian Cancer, 32nd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S223-S223, ISSN: 1619-7070

Conference paper

Trousil S, Lee P, Edwards RJ, Maslen L, Lozan-Kuehne JP, Ramaswami R, Aboagye EO, Clarke S, Liddle C, Sharma Ret al., 2019, Altered cytochrome 2E1 and 3A P450-dependent drug metabolism in advanced ovarian cancer correlates to tumour-associated inflammation, British Journal of Pharmacology, Vol: 176, Pages: 3712-3722, ISSN: 0007-1188

Background and PurposePrevious work has focussed on changes in drug metabolism caused by altered activity of CYP3A in the presence of inflammation and, in particular, inflammation associated with malignancy. However, drug metabolism involves a number of other P450s, and therefore, we assessed the effect of cancer‐related inflammation on multiple CYP enzymes using a validated drug cocktail.Experimental ApproachPatients with advanced stage ovarian cancer and healthy volunteers were recruited. Participants received caffeine, chlorzoxazone, dextromethorphan, and omeprazole as in vivo probes for CYP1A2, CYP2E1, CYP2D6, CYP3A, and CYP2C19. Blood was collected for serum C‐reactive protein and cytokine analysis.Key ResultsCYP2E1 activity was markedly up‐regulated in cancer (6‐hydroxychlorzoxazone/chlorzoxazone ratio of 1.30 vs. 2.75), while CYP3A phenotypic activity was repressed in cancer (omeprazole sulfone/omeprazole ratio of 0.23 vs. 0.49). Increased activity of CYP2E1 was associated with raised serum levels of IL‐6, IL‐8, and TNF‐α. Repression of CYP3A correlated with raised levels of serum C‐reactive protein, IL‐6, IL‐8, and TNF‐α.Conclusions and ImplicationsCYP enzyme activity is differentially affected by the presence of tumour‐associated inflammation, affecting particularly CYP2E1‐ and CYP3A‐mediated drug metabolism, and may have profound implications for drug development and prescribing in oncological settings.

Journal article

Brickute D, Kaliszczak M, Barnes C, Lau D, Carroll L, Stevens E, Trousil S, Alam I, Nguyen QD, Aboagye Eet al., 2019, Development and evaluation of an 18F-radiolabeled monocyclam derivative for imaging CXCR4 expression, Molecular Pharmaceutics, Vol: 16, Pages: 2106-2117, ISSN: 1543-8384

In humans, C–X–C chemokine receptor type 4 (CXCR4) is a protein that is encoded by the CXCR4 gene and binds the ligand CXCL12 (also known as SDF-1). The CXCR4–CXCL12 interaction in cancer elicits biological activities that result in tumor progression and has accordingly been the subject of significant investigation for detection and treatment of the disease. Peptidic antagonists have been labeled with a variety of radioisotopes for the detection of CXCR4, but the methodology utilizing small molecules has predominantly used radiometals. We report here the development of a 18F-radiolabeled cyclam-based small molecule radioprobe, [18F]MCFB, for imaging CXCR4 expression. The IC50 value of [19F]MCFB for CXCR4 was similar to that of AMD3465 (111.3 and 89.8 nM, respectively). In vitro binding assays show that the tracer depicted a differential CXCR4 expression, which was blocked in the presence of AMD3465, demonstrating the specificity of [18F]MCFB. Positron emission tomography (PET) imaging studies showed a distinct uptake of the radioprobe in lymphoma and breast cancer xenografts. High liver and kidney uptakes were seen with [18F]MCFB, leading us to further examine the basis of its pharmacokinetics in relation to the tracer’s cationic nature and thus the role of organic cation transporters (OCTs). Substrate competition following the intravenous injection of metformin led to a marked decrease in the urinary excretion of [18F]MCFB, with moderate changes observed in other organs, including the liver. Our results suggest involvement of OCTs in the renal elimination of the tracer. In conclusion, the 18F-radiolabeled monocyclam, [18F]MCFB, has potential to detect tumor CXCR4 in nonhepatic tissues.

Journal article

Hernandez-Gil J, Braga M, Harriss B, Carroll LS, Leow CH, Tang M-X, Aboagye EO, Long NJet al., 2019, Development of Ga-68-labelled ultrasound microbubbles for whole-body PET imaging, Chemical Science, Vol: 10, Pages: 5603-5615, ISSN: 2041-6520

Microbubble (MB) contrast agents have revolutionalised the way ultrasound (US) imaging can be used clinically and pre-clinically. Contrast-enhanced US offers improvements in soft-tissue contrast, as well as the ability to visualise disease processes at the molecular level. However, its inability to provide in vivo whole-body imaging can hamper the development of new MB formulations. Herein, we describe a fast and efficient method for achieving 68Ga-labelling of MBs after a direct comparison of two different strategies. The optimised approach produces 68Ga-labelled MBs in good yields through the bioorthogonal inverse-electron-demand Diel–Alder reaction between a trans-cyclooctene-modified phospholipid and a new tetrazine-bearing HBED-CC chelator. The ability to noninvasively study the whole-body distribution of 68Ga-labelled MBs was demonstrated in vivo using positron emission tomography (PET). This method could be broadly applicable to other phospholipid-based formulations, providing accessible solutions for in vivo tracking of MBs.

Journal article

Lavdas I, Glocker B, Rueckert D, Taylor SA, Aboagye EO, Rockall AGet al., 2019, Machine learning in whole-body MRI: experiences and challenges from an applied study using multicentre data, Clinical Radiology, Vol: 74, Pages: 346-356, ISSN: 0009-9260

Machine learning is now being increasingly employed in radiology to assist with tasks such as automatic lesion detection, segmentation, and characterisation. We are currently involved in an National Institute of Health Research (NIHR)-funded project, which aims to develop machine learning methods to improve the diagnostic performance and reduce the radiology reading time of whole-body magnetic resonance imaging (MRI) scans, in patients being staged for cancer (MALIBO study). We describe here the main challenges we have encountered during the course of this project. Data quality and uniformity are the two most important data traits to be considered in clinical trials incorporating machine learning. Robust data pre-processing and machine learning pipelines have been employed in MALIBO, a task facilitated by the now freely available machine learning libraries and toolboxes. Another important consideration for achieving the desired clinical outcome in MALIBO, was to effectively host the resulting machine learning output, along with the clinical images, for reading in a clinical environment. Finally, a range of legal, ethical, and clinical acceptance issues should be considered when attempting to incorporate computer-assisting tools into clinical practice. The road from translating computational methods into potentially useful clinical tools involves an analytical, stepwise adaptation approach, as well as engagement of a multidisciplinary team.

Journal article

Leow CH, Bush N, Stanziola A, Braga M, Shah A, Hernández-Gil J, Long NJ, Aboagye E, Bamber J, Tang Met al., 2019, 3D microvascular imaging using high frame rate ultrasound and ASAP without contrast agents: development and initial in vivo evaluation on non-tumour and tumour models, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, Vol: 66, Pages: 939-948, ISSN: 0885-3010

Three-dimensional imaging is valuable to non-invasively assess angiogenesis given the complex 3D architecture of vascular networks. The emergence of high frame rate (HFR) ultrasound, which can produce thousands of images per second, has inspired novel signal processing techniques and their applications in structural and functionalimaging of blood vessels. Although highly sensitive vascular mapping has been demonstrated using ultrafast Doppler, the detectability of microvasculature from the background noise may be hindered by the low signal to noise ratio (SNR) particularly in deeper region and without the use of contrast agents. We have recently demonstrated a coherence based technique, acoustic sub-aperture imaging (ASAP), for super-contrast vascular imaging and illustrated the contrast improvement using HFR contrast-enhanced ultrasound. In this work, we provide a feasibility study for microvascular imaging using ASAP without contrast agents, and extend its capability from 2D to volumetric vascular mapping. Using an ultrasound research system and a pre-clinical probe, we demonstrated the improved visibility of microvascular mapping using ASAP in comparison to ultrafast Power Doppler (PD) on a mouse kidney, liver and tumour without contrast agent injection. The SNR of ASAP images improves in average by 10dB when compared to PD. Besides, directional velocity mappings were also demonstrated by combining ASAP with the phase information extracted from lag-1 autocorrelation. Three-dimensional vascular and velocity mapping of the mouse kidney, liver and tumour were demonstrated by stackingthe ASAP images acquired using 2D ultrasound imaging and a trigger-controlled linear translation stage. The 3D results depicted clear micro-vasculature morphologies and function

Journal article

Ferris T, Carroll L, Mease RC, Spivey AC, Aboagye EOet al., 2019, Iodination of terminal alkynes using KI/CuSO4 – A facile method with potential for radio-iodination, Tetrahedron Letters, Vol: 60, Pages: 936-939, ISSN: 0040-4039

Herein, we report an efficient new method for the iodination of terminal alkynes using stoichiometric KI and CuSO4 in a mix of acetonitrile and acetate buffer that holds promise for further development into a method for radio-iodination.

Journal article

Pinato D, Brown MW, Trousil S, Aboagye E, Beaumont J, Zhang H, Coley HM, Mauri F, Sharma Ret al., 2019, Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma., British Journal of Cancer, Vol: 120, Pages: 512-521, ISSN: 0007-0920

Background: Aberrant activation of Axl is implicated in the progression of HCC. We explored biologic significance and preclinical efficacy of Axl inhibition as a therapeutic strategy in sorafenib-naïve and resistant HCC.Methods: We evaluated Axl expression in sorafenib-naïve and resistant (SR) clones of epithelial (HuH7) and mesenchymal origin (SKHep-1) using antibody arrays and confirmed tissue expression. We tested the effect of Axl inhibition with RNA-interference and pharmacologically with R428 on a number of phenotypic assays. Results: Axl mRNA overexpression in cell lines (n=28) and RNA-seq tissue datasets (n=373) correlated with epithelial-to-mesenchymal transition (EMT). Axl was overexpressed in HCC compared to cirrhosis and normal liver. We confirmed sorafenib-resistance to be associated with EMT and enhanced motility in both HuH7-SR and SKHep-1-SR cells documenting a 4-fold increase in Axl phosphorylation as an adaptive feature of chronic sorafenib treatment in SKHep-1-SR cells. Axl inhibition reduced motility and enhanced sensitivity to sorafenib in SKHep-1SR cells. In patients treated with sorafenib (n=40) circulating Axl levels correlated with shorter survival.Conclusions: Suppression of Axl-dependent signaling influences the transformed phenotype in HCC cells and contributes to adaptive resistance to sorafenib, providing a pre-clinical rationale for the development of Axl inhibitors as a measure to overcome sorafenib resistance.

Journal article

Allott L, Barnes C, Brickute D, Aboagye EOet al., 2019, An improved automated radiosynthesis of [F-18]FET-beta AG-TOCA, Reaction Chemistry and Engineering, Vol: 4, Pages: 569-574, ISSN: 2058-9883

The fluorine-18 radiolabelled octreotide derivative [18F]FET-βAG-TOCA targeting somatostatin receptor type 2, has been evaluated clinically for positron emission tomography (PET) imaging of neuroendocrine tumours (NETs). We report an improved automated radiosynthesis of [18F]FET-βAG-TOCA with several advantages over the current automated GMP synthesis: 1) cartridge-based purification of 2-[18F]fluoroethylazide ([18F]FEA); 2) simple set-up for the radiolabelling on a single cassette; 3) HPLC purification using a biocompatible mobile phase. [18F]FET-βAG-TOCA was produced with a radiochemical yield of 16.7 ± 0.6% (non-decay corrected) and radiochemical purity ≥98%. The automated synthesis produced multi-patient doses (900 MBq) that were radiochemically stable (≥98%) over 4 hours. In addition, the automated procedure described can be used, with minimal adaptation, to radiolabel any alkyne-containing peptide with [18F]FEA using the GE FASTlab™ platform.

Journal article

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