338 results found
Witney TH, Fortt RR, Aboagye EO, 2014, Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by F-18-ICMT-11-Positron Emission Tomography, PLOS ONE, Vol: 9, ISSN: 1932-6203
Witney TH, Carroll L, Alam IS, et al., 2014, A Novel Radiotracer to Image Glycogen Metabolism in Tumors by Positron Emission Tomography, CANCER RESEARCH, Vol: 74, Pages: 1319-1328, ISSN: 0008-5472
Carroll L, Aboagye EO, 2014, A manganese-catalysed oxidative benzylic C-H F-18-fluorination for applications in drug development, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, Vol: 57, Pages: 181-181, ISSN: 0362-4803
Aboagye EO, Aigbirhio FI, Allen P, et al., 2014, Abstracts of the 22nd International Isotope Society (UK Group) Symposium: synthesis and applications of labelled compounds 2013., J Labelled Comp Radiopharm, Vol: 57, Pages: 178-190
Meeting Summary The 22nd annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK, on Friday, 18 October 2013. The meeting was attended by 65 delegates from academia and industry; the life sciences; and chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral and poster presentations on isotopic chemistry and applications of labelled compounds, or of chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium programme was divided into a morning session chaired by Dr Karl Cable (GlaxoSmithKline, UK) and afternoon sessions chaired by Mr Mike Chappelle (Quotient Biosciences, UK) and by Dr Nick Bushby (AstraZeneca, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).
Challapalli A, Sharma R, Hallett WA, et al., 2014, Biodistribution and Radiation Dosimetry of Deuterium-Substituted F-18-Fluoromethyl-[1, 2-H-2(4)]Choline in Healthy Volunteers, JOURNAL OF NUCLEAR MEDICINE, Vol: 55, Pages: 256-263, ISSN: 0161-5505
Pisaneschi F, Slade RL, Iddon L, et al., 2014, Synthesis of a new fluorine-18 glycosylated 'click' cyanoquinoline for the imaging of epidermal growth factor receptor, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, Vol: 57, Pages: 92-96, ISSN: 0362-4803
George GPC, Stevens E, Aberg O, et al., 2014, Preclinical evaluation of a CXCR4-specific Ga-68-labelled TN14003 derivative for cancer PET imaging, BIOORGANIC & MEDICINAL CHEMISTRY, Vol: 22, Pages: 796-803, ISSN: 0968-0896
Gallo J, Alam IS, Jin J, et al., 2014, PET imaging with multimodal upconversion nanoparticles, DALTON TRANSACTIONS, Vol: 43, Pages: 5535-5545, ISSN: 1477-9226
Challapalli A, Barwick T, Tomasi G, et al., 2014, Exploring the potential of [C-11]choline-PET/CT as a novel imaging biomarker for predicting early treatment response in prostate cancer, NUCLEAR MEDICINE COMMUNICATIONS, Vol: 35, Pages: 20-29, ISSN: 0143-3636
Merchant S, Witney TH, Aboagye EO, 2014, Imaging as a pharmacodynamic and response biomarker in cancer, Clinical and Translational Imaging, Vol: 2, Pages: 13-31, ISSN: 2281-5872
Imaging of biological and molecular processes has provided the platform for evaluating the hallmarks of cancer, such as metabolism, proliferation, tissue invasion, angiogenesis, apoptosis and hypoxia, and in turn for assessing the efficacy of treatments including novel targeted therapies. Cross-sectional imaging methods can measure response to chemotherapy and radiotherapy by measuring changes in tumour volume. Imaging modalities such as positron emission tomography and functional magnetic resonance imaging can non-invasively detect early molecular changes in response to therapy, provide guidance for therapy optimisation, and predict response to treatments and clinical outcome. In an era of escalating drug trial costs, with high attrition rates of early-phase studies, the development of an imaging biomarker can contribute to optimisation of proof of concept and patient stratification. In this review, we examine the current molecular imaging modalities used to assess pharmacodynamics and therapy response and highlight some novel emerging imaging strategies. © 2014 Italian Association of Nuclear Medicine and Molecular Imaging.
Lake MC, Aboagye EO, 2014, Luciferase fragment complementation imaging in preclinical cancer studies., Oncoscience, Vol: 1, Pages: 310-325, ISSN: 2331-4737
The luciferase fragment complementation assay (LFCA) enables molecular events to be non-invasively imaged in live cells in vitro and in vivo in a comparatively cheap and safe manner. It is a development of previous enzyme complementation assays in which reporter genes are split into two, individually enzymatically inactive, fragments that are able to complement one another upon interaction. This complementation can be used to externally visualize cellular activities. In recent years, the number of studies which have used LFCAs to probe questions relevant to cancer have increased, and this review summarizes the most significant and interesting of these. In particular, it focuses on work conducted on the epidermal growth factor, nuclear and chemokine receptor families, and intracellular signaling pathways, including IP3, cAMP, Akt, cMyc, NRF2 and Rho GTPases. LFCAs which have been developed to image DNA methylation and detect RNA transcripts are also discussed.
Gallo J, Alam IS, Lavdas I, et al., 2013, RGD-targeted MnO nanoparticles as T1 contrast agents for cancer imaging – the effect of PEG length in vivo, J. Mater. Chem. B
As magnetic resonance imaging (MRI) contrast agents, T1 Gd3+ chelates are generally the preferred option for radiologists over T2 iron oxide nanoparticles. The main reason for the popularity of T1 agents is the easier interpretation of T1-weighted MR images. However, the chemical versatility of nanoparticulate platforms makes them ideal candidates for the next generation of targeted MRI contrast agents. In this context, we present herein the design and preparation of a nanoparticulate contrast agent based on MnO, which presents T1 contrast enhancement properties as well as nanoparticle formulation. Functionalization of MnO nanoparticles with the extensively studied RGD peptide was used to target tumours over-expressing the αvβ3 integrin. PEG (polyethylene glycol) molecules were used to increase the blood half-life of the nanoparticles in vivo, and the effect of different PEG lengths on the final contrast on MR images was investigated.
Kaliszczak M, Pardo OE, Seckl MJ, et al., 2013, HDAC6 inhibitor C1A abrogates the recruitment of the autophagic machinery and synergizes with proteasome, src kinase, and PI3K-mTOR inhibition., MOLECULAR CANCER THERAPEUTICS, Vol: 12, ISSN: 1535-7163
Trousil S, Hoppmann S, Nguyen Q-D, et al., 2013, Positron emission tomography imaging of HER2 expression and pharmacodynamic response to HSP90 inhibition with the next-generation ZHER2:2891 Affibody molecule [18F]GE-226., MOLECULAR CANCER THERAPEUTICS, Vol: 12, ISSN: 1535-7163
Eccles SA, Aboagye EO, Ali S, et al., 2013, Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer, Breast Cancer Research, Vol: 15, Pages: R-R, ISSN: 1465-542X
IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease
Pisaneschi F, Witney TH, Iddon L, et al., 2013, Synthesis of [F-18]fluoro-pivalic acid: an improved PET imaging probe for the fatty acid synthesis pathway in tumours, MEDCHEMCOMM, Vol: 4, Pages: 1350-1353, ISSN: 2040-2503
Kaliszczak M, Patel H, Kroll SHB, et al., 2013, Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance, British Journal of Cancer, Vol: 109, Pages: 2356-2367, ISSN: 1532-1827
background: Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy.methods: We generated drug-resistant cells by continuous low-dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy.results: We identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 Å2) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively.conclusion: We identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer.
Carroll L, Evans HL, Aboagye EO, et al., 2013, Bioorthogonal chemistry for pre-targeted molecular imaging - progress and prospects, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 11, Pages: 5772-5781, ISSN: 1477-0520
Challapalli A, Kenny LM, Hallett WA, et al., 2013, F-18-ICMT-11, a Caspase-3-Specific PET Tracer for Apoptosis: Biodistribution and Radiation Dosimetry, JOURNAL OF NUCLEAR MEDICINE, Vol: 54, Pages: 1551-1556, ISSN: 0161-5505
Dart DA, Waxman J, Aboagye EO, et al., 2013, Visualising Androgen Receptor Activity in Male and Female Mice, PLOS One, Vol: 8, ISSN: 1932-6203
Androgens, required for normal development and fertility of males and females, have vital roles in the reproductivetract, brain, cardiovascular system, smooth muscle and bone. Androgens function via the androgen receptor (AR), aligand-dependent transcription factor. To assay and localise AR activity in vivo we generated the transgenic “ARELuc”mouse, expressing a luciferase reporter gene under the control of activated endogenous AR. In vivo imaging ofandrogen-mediated luciferase activity revealed several strongly expressing tissues in the male mouse as expectedand also in certain female tissues. In males the testes, prostate, seminal vesicles and bone marrow all showed highAR activity. In females, strong activity was seen in the ovaries, uterus, omentum tissue and mammary glands. In bothsexes AR expression and activity was also found in salivary glands, the eye (and associated glands), adipose tissue,spleen and, notably, regions of the brain. Luciferase protein expression was found in the same cell layers asandrogen receptor expression. Additionally, mouse AR expression and activity correlated well with AR expression inhuman tissues. The anti-androgen bicalutamide reduced luciferase signal in all tissues. Our model demonstrates thatandrogens can act in these tissues directly via AR, rather than exclusively via androgen aromatisation to estrogensand activation of the estrogen receptor. Additionally, it visually demonstrates the fundamental importance of ARsignalling outside the normal role in the reproductive organs. This model represents an important tool forphysiological and developmental analysis of androgen signalling, and for characterization of known and novelandrogenic or antiandrogenic compounds.
Tomasi G, Aboagye EO, 2013, Introduction to the analysis of PET data in oncology, JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, Vol: 40, Pages: 419-436, ISSN: 1567-567X
George GPC, Pisaneschi F, Stevens E, et al., 2013, Scavenging strategy for specific activity improvement: application to a new CXCR4-specific cyclopentapeptide positron emission tomography tracer, J. Label Compd. Radiopharm.
Huisgen cycloaddition is attractive to label peptide because of its rapidity and bioorthogonality. However, for larger tracers, the physico-chemical differences between the precursor and the tracer are usually insufficient to allow their separation by HPLC, reducing the specific activity. This is of importance for peptidic tracers because the combination of their high-affinity receptor with low specific activity results in the precursor saturating the receptors, causing non-specific tracer binding. Here, we report a fast, one-pot, general strategy to circumvent this issue, yielding a tracer of improved specific activity. It consists in adding a lipophilic azide after the labeling step to scavenge unreacted precursor into a more lipophilic species that does not co-elute with the tracer. We applied this strategy to a new fluorinated cyclopentapeptidic CXCR4 antagonist for the PET imaging of cancer, CCIC15, for which we managed to reduce the apparent peptide concentration by a factor of 34 in 10 min. This tracer was radiolabeled by click chemistry with 2-[18F]fluoroethylazide, yielding the tracer in 18 ±6% (n = 5) end-of-synthesis radiochemical yields (EOS-RCY) in 1.5 h from [18F]fluoride with a specific activity of 19.4 GBq μmol 1. Preliminary biological evaluation of the probe confirmed potency and specificity for CXCR4; further biological evaluation is underway.
Nguyen QD, Lavdas I, Gubbins J, et al., 2013, Temporal and Spatial Evolution of Therapy-Induced Tumor Apoptosis Detected by Caspase-3-Selective Molecular Imaging, Clinical Cancer Research, Vol: 19, Pages: 3914-3924
Zhao L, Ashek A, Wang L, et al., 2013, Heterogeneity in lung 18FDG uptake in PAH: potential of dynamic 18FDG-PET with kinetic analysis as a bridging biomarker for pulmonary remodeling targeted treatments, Circulation
George GPC, Stevens E, Pisaneschi F, et al., 2013, Synthesis, radiolabelling and biological evaluation of new PET probes for CXCR4-specific imaging, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, Vol: 56, Pages: S409-S409, ISSN: 0362-4803
Evans HL, Carroll L, Nguyen Q-D, et al., 2013, Copper-free 'click' chemistry as a potential pre-targeting tool for PET imaging, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, Vol: 56, Pages: S204-S204, ISSN: 0362-4803
Sala R, Quang-De N, Patel C, et al., 2013, Regulation of 18F-fluorothymidine uptake by thymidine kinase 1 protein phosphorylation., 104th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Coombes RC, Tat T, Miller ML, et al., 2013, An open-label study of lapatinib in women with HER-2-negative early breast cancer: the lapatinib pre-surgical study (LPS study), ANNALS OF ONCOLOGY, Vol: 24, Pages: 924-930, ISSN: 0923-7534
Carroll L, Witney TH, Aboagye EO, 2013, Design and synthesis of novel F-18-radiolabelled glucosamine derivatives for cancer imaging, MEDCHEMCOMM, Vol: 4, Pages: 653-656, ISSN: 2040-2503
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