351 results found
Aboagye EO, Challapalli A, 2016, Positron emission tomography imaging of tumor cell metabolism and application to therapy response monitoring, Frontiers in Oncology, Vol: 6, ISSN: 2234-943X
Cancer cells do reprogram their energy metabolism to enable several functions, such as generation of biomass including membrane biosynthesis, and overcoming bioenergetic and redox stress. In this article, we review both established and evolving radioprobes developed in association with positron emission tomography (PET) to detect tumor cell metabolism and effect of treatment. Measurement of enhanced tumor cell glycolysis using 2-deoxy-2-[18F]fluoro-D-glucose is well established in the clinic. Analogs of choline, including [11C]choline and various fluorinated derivatives are being tested in several cancer types clinically with PET. In addition to these, there is an evolving array of metabolic tracers for measuring intracellular transport of glutamine and other amino acids or for measuring glycogenesis, as well as probes used as surrogates for fatty acid synthesis or precursors for fatty acid oxidation. In addition to providing us with opportunities for examining the complex regulation of reprogramed energy metabolism in living subjects, the PET methods open up opportunities for monitoring pharmacological activity of new therapies that directly or indirectly inhibit tumor cell metabolism.
Alam IS, Arrowsmith RL, Cortezon-Tamarit F, et al., 2016, Correction: Microwave gallium-68 radiochemistry for kinetically stable bis(thiosemicarbazone) complexes: structural investigations and cellular uptake under hypoxia, Dalton Transactions, Vol: 45, Pages: 3650-3650, ISSN: 1477-9226
Mazarico JM, Sánchez-Arévalo Lobo VJ, Favicchio R, et al., 2016, Choline Kinase Alpha (CHKα) as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma: Expression, Predictive Value, and Sensitivity to Inhibitors., Molecular Cancer Therapeutics, Vol: 15, Pages: 323-333, ISSN: 1538-8514
Choline kinase α (CHKα) plays a crucial role in the regulation of membrane phospholipid synthesis and has oncogenic properties in vitro. We have analyzed the expression of CHKα in cell lines derived from pancreatic ductal adenocarcinoma (PDAC) and have found increased CHKα expression, associated with differentiation. CHKα protein expression was directly correlated with sensitivity to MN58b, a CHKα inhibitor that reduced cell growth through the induction of apoptosis. Accordingly, CHKα knockdown led to reduced drug sensitivity. In addition, we found that gemcitabine-resistant PDAC cells displayed enhanced sensitivity to CHKα inhibition and, in vitro, MN58b had additive or synergistic effects with gemcitabine, 5-fluorouracil, and oxaliplatin, three active drugs in the treatment of PDAC. Using tissue microarrays, CHKα was found to be overexpressed in 90% of pancreatic tumors. While cytoplasmic CHKα did not relate to survival, nuclear CHKα distribution was observed in 43% of samples and was associated with longer survival, especially among patients with well/moderately differentiated tumors. To identify the mechanisms involved in resistance to CHKα inhibitors, we cultured IMIM-PC-2 cells with increasingly higher concentrations of MN58b and isolated a subline with a 30-fold higher IC50. RNA-Seq analysis identified upregulation of ABCB1 and ABCB4 multidrug resistance transporters, and functional studies confirmed that their upregulation is the main mechanism involved in resistance. Overall, our findings support the notion that CHKα inhibition merits further attention as a therapeutic option in patients with PDAC and that expression levels may predict response. Mol Cancer Ther; 15(2); 323-33. ©2016 AACR.
Alam IS, Arrowsmith RL, Cortezon-Tamarit F, et al., 2016, Microwave gallium-68 radiochemistry for kinetically stable bis(thiosemicarbazone) complexes: structural investigations and cellular uptake under hypoxia, Dalton Transactions, Vol: 45, Pages: 144-155, ISSN: 1477-9226
We report the microwave synthesis of several bis(thiosemicarbazones) and the rapid gallium-68 incorporation to give the corresponding metal complexes. These proved kinetically stable under ‘cold’ and ‘hot’ biological assays and were investigated using laser scanning confocal microscopy, flow cytometry and radioactive cell retention studies under normoxia and hypoxia. 68Ga complex retention was found to be 34% higher in hypoxic cells than in normoxic cells over 30 min, further increasing to 53% at 120 min. Our data suggests that this class of gallium complexes show hypoxia selectivity suitable for imaging in living cells and in vivo tests by microPET in nude athymic mice showed that they are excreted within 1 h of their administration.
Hopkins TG, Blagden S, Mura M, et al., 2015, The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer, Nucleic Acids Research, Vol: 44, Pages: 1227-1246, ISSN: 1362-4962
RNA-binding proteins (RBPs) are increasingly identifiedas post-transcriptional drivers of cancer progression.The RBP LARP1 is an mRNA stability regulator,and elevated expression of the protein in hepatocellularand lung cancers is correlated with adverseprognosis. LARP1 associates with an mRNA interactomethat is enriched for oncogenic transcripts.Here we explore the role of LARP1 in epithelial ovariancancer, a disease characterized by the rapid acquisitionof resistance to chemotherapy through theinduction of pro-survival signalling. We show, usingovarian cell lines and xenografts, that LARP1 is requiredfor cancer cell survival and chemotherapy resistance.LARP1 promotes tumour formation in vivoand maintains cancer stem cell-like populations. Usingtranscriptomic analysis following LARP1 knockdown,cross-referenced against the LARP1 interactome,we identify BCL2 and BIK as LARP1 mRNAtargets. We demonstrate that, through an interactionwith the 3 untranslated regions (3 UTRs) of BCL2and BIK, LARP1 stabilizes BCL2 but destabilizes BIKwith the net effect of resisting apoptosis. Together,our data indicate that by differentially regulating thestability of a selection of mRNAs, LARP1 promotesovarian cancer progression and chemotherapy resistance.
Sharma R, Kallur KG, Ryu JS, et al., 2015, Multicenter Reproducibility of F-18-Fluciclatide PET Imaging in Subjects with Solid Tumors, JOURNAL OF NUCLEAR MEDICINE, Vol: 56, Pages: 1855-1861, ISSN: 0161-5505
Allott L, Smith G, Aboagye EO, et al., 2015, PET imaging of steroid hormone receptor expression, Molecular Imaging, Vol: 14, Pages: 534-550, ISSN: 1536-0121
Da Pieve C, Allott L, Martins CD, et al., 2015, Strategies for the development of high specific activity affibody based probes for the detection of HER3 positive tumours, 28th Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S247-S248, ISSN: 1619-7070
Challapalli A, Trousil S, Hazell S, et al., 2015, Exploiting altered patterns of choline kinase-alpha expression on human prostate tissue to prognosticate prostate cancer, JOURNAL OF CLINICAL PATHOLOGY, Vol: 68, Pages: 703-709, ISSN: 0021-9746
Mapelli P, Aboagye EO, Stebbing J, et al., 2015, Epigenetic changes in gastroenteropancreatic neuroendocrine tumours, ONCOGENE, Vol: 34, Pages: 4439-4447, ISSN: 0950-9232
Lavdas I, Rockall AG, Castelli F, et al., 2015, Apparent Diffusion Coefficient of Normal Abdominal Organs and Bone Marrow From Whole-Body DWI at 1.5 T: The Effect of Sex and Age, AMERICAN JOURNAL OF ROENTGENOLOGY, Vol: 205, Pages: 242-250, ISSN: 0361-803X
Doepner AM, Aboagye EO, Barrett AGM, 2015, 2 '-Deoxy-2 ',2 '-difluorothymidine analogues for radiolabeling with fluorine-18 and other biomedical applications, TETRAHEDRON LETTERS, Vol: 56, Pages: 3293-3297, ISSN: 0040-4039
Carroll L, Evans H, Spivey AC, et al., 2015, Mn-salen catalysed benzylic C-H activation for the synthesis of aryl [(18)F]CF3-containing PET probes., Chemical Communications, Vol: 51, Pages: 8439-8441, ISSN: 1364-548X
The development of a Mn-salen complex catalysed oxidative benzylic fluorination of non-activated C-H bonds using [(18)F]fluoride is described for installation of [(18)F]CHRF, [(18)F]CR2F and particularly [(18)F]CF3 containing groups in the presence of other functional groups.
Merchant S, Aboagye EO, Lim A, et al., 2015, Evaluation of apoptosis in breast cancer using the novel PET probe [F-18]ICMT-11 in patients treated with neoadjuvant FEC chemotherapy: Initial assessment of optimum imaging time and relation to caspase-3 immunostaining, 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Challapalli A, Barwick T, Pearson RA, et al., 2015, 3 '-Deoxy-3 '-F-18-fluorothymidine positron emission tomography as an early predictor of disease progression in patients with advanced and metastatic pancreatic cancer, EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, Vol: 42, Pages: 831-840, ISSN: 1619-7070
Saleem A, Searle GE, Kenny LM, et al., 2015, Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer, EJNMMI Research, Vol: 5, ISSN: 2191-219X
BackgroundBrain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access.MethodsPatients with Her-2+ metastatic breast cancer either with at least one 1-cm diameter brain metastasis or without brain metastases underwent dynamic carbon-11 radiolabelled lapatinib ([11C]lapatinib)-PET. Less than 20 μg of [11C]lapatinib was administered before and after 8 days of oral lapatinib (1,500 mg once daily). Radial arterial blood sampling was performed throughout the 90-min scan. The contribution of blood volume activity to the tissue signal was excluded to calculate lapatinib uptake in normal brain and metastases. Partitioning of radioactivity between plasma and tissue (V T) was calculated and the tissue concentration of lapatinib derived. Plasma lapatinib levels were measured and adverse events noted.ResultsSix patients (three with brain metastases) were recruited. About 80% plasma radioactivity corresponded to intact [11C]lapatinib after 60 min. PET signal in the brain corresponded to circulating radioactivity levels, with no [11C]lapatinib uptake observed in normal brain tissue. In contrast, radioactivity uptake in cranial metastases was significantly higher (p = 0.002) than that could be accounted by circulating radioactivity levels, consistent with [11C]lapatinib uptake in brain metastases. There was no difference in lapatinib uptake between the baseline and day 8 scans, suggesting no effect of increased drug access by inhibition of the drug efflux proteins by therapeutic doses of lapatinib.ConclusionsIncreased lapatinib uptake was observed in brain metastases but not in normal brain.
Hoyng LL, Frings V, Hoekstra OS, et al., 2015, Metabolically active tumour volume segmentation from dynamic [F-18] FLT PET studies in non-small cell lung cancer, EJNMMI RESEARCH, Vol: 5, ISSN: 2191-219X
Alam IS, Arshad MA, Quang-De N, et al., 2015, Radiopharmaceuticals as probes to characterize tumour tissue, EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, Vol: 42, Pages: 537-561, ISSN: 1619-7070
AbuAli G, Chaisaklert W, Stelloo E, et al., 2015, The anticancer gene ORCTL3 targets stearoyl-CoA desaturase-1 for tumour-specific apoptosis, ONCOGENE, Vol: 34, Pages: 1718-1728, ISSN: 0950-9232
George GPC, Pisaneschi F, Quang-De N, et al., 2015, Positron Emission Tomographic Imaging of CXCR4 in Cancer: Challenges and Promises, MOLECULAR IMAGING, Vol: 14, ISSN: 1536-0121
Schug ZT, Peck B, Jones DT, et al., 2015, Acetyl-CoA Synthetase 2 Promotes Acetate Utilization and Maintains Cancer Cell Growth under Metabolic Stress, CANCER CELL, Vol: 27, Pages: 57-71, ISSN: 1535-6108
Udemba A, Smith G, Nguyen Q-D, et al., 2015, Design, synthesis and initial characterisation of a radiolabelled [F-18]pyrimidoindolone probe for detecting activated caspase-3/7, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 13, Pages: 5418-5423, ISSN: 1477-0520
Mura M, Hopkins TG, Michael T, et al., 2014, LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression, Oncogene, Vol: 34, Pages: 5025-5036, ISSN: 1476-5594
RNA-binding proteins (RBPs) bind to and post-transcriptionally regulate the stability of mRNAs. La-related protein 1 (LARP1) is a conserved RBP that interacts with poly-A-binding protein and is known to regulate 5′-terminal oligopyrimidine tract (TOP) mRNA translation. Here, we show that LARP1 is complexed to 3000 mRNAs enriched for cancer pathways. A prominent member of the LARP1 interactome is mTOR whose mRNA transcript is stabilized by LARP1. At a functional level, we show that LARP1 promotes cell migration, invasion, anchorage-independent growth and in vivo tumorigenesis. Furthermore, we show that LARP1 expression is elevated in epithelial cancers such as cervical and non-small cell lung cancers, where its expression correlates with disease progression and adverse prognosis, respectively. We therefore conclude that, through the post-transcriptional regulation of genes such as mTOR within cancer pathways, LARP1 contributes to cancer progression.
Pazarentzos E, Mahul-Mellier A-L, Datler C, et al., 2014, I kappa B alpha inhibits apoptosis at the outer mitochondrial membrane independently of NF-kappa B retention, EMBO JOURNAL, Vol: 33, Pages: 2814-2828, ISSN: 0261-4189
Trousil S, Lee P, Pinato DJ, et al., 2014, Alterations of Choline Phospholipid Metabolism in Endometrial Cancer Are Caused by Choline Kinase Alpha Overexpression and a Hyperactivated Deacylation Pathway, CANCER RESEARCH, Vol: 74, Pages: 6867-6877, ISSN: 0008-5472
Willaime JMY, Aboagye EO, Tsoumpas C, et al., 2014, A multifractal approach to space-filling recovery for PET quantification, MEDICAL PHYSICS, Vol: 41, ISSN: 0094-2405
Filipovic A, Lombardo Y, Faronato M, et al., 2014, Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells (vol 148, pg 455, 2014), BREAST CANCER RESEARCH AND TREATMENT, Vol: 148, Pages: 463-463, ISSN: 0167-6806
Filipovic A, Lombardo Y, Fronato M, et al., 2014, Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells, BREAST CANCER RESEARCH AND TREATMENT, Vol: 148, Pages: 455-462, ISSN: 0167-6806
Kenny LM, Aboagye EO, 2014, Clinical Translation of Molecular Imaging Agents Used in PET Studies of Cancer, EMERGING APPLICATIONS OF MOLECULAR IMAGING TO ONCOLOGY, Vol: 124, Pages: 329-374, ISSN: 0065-230X
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