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Morran D.C.,Cancer Research UK Research Institute | Wu J.,Garvan Institute of Medical Research | Jamieson N.B.,Royal Infirmary | Mrowinska A.,Cancer Research UK Research Institute | And 29 more authors.
Gut | Year: 2014

Objective: Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease. Design Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of Kras G12Ddriven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition. Results: We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours. Conclusions: KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future.


McCluskey A.G.,University of Strathclyde | Mairs R.J.,University of Glasgow | Tesson M.,University of Glasgow | Pimlott S.L.,West of Scotland Radionuclide Dispensary | And 4 more authors.
Journal of Nuclear Medicine | Year: 2012

Targeted radiotherapy using 131I-metaiodobenzylguanidine ( 131I-MIBG) has produced remissions in some neuroblastoma patients. We previously reported that combining 131I-MIBG with the topoisomerase I inhibitor topotecan induced long-term DNA damage and supraadditive toxicity to noradrenaline transporter (NAT)-expressing cells and xenografts. This combination treatment is undergoing clinical evaluation. This present study investigated the potential of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP-1) inhibition, in vitro and in vivo, to further enhance 131I-MIBG/topotecan efficacy. Methods: Combinations of topotecan and the PARP-1 inhibitor PJ34 were assessed for synergism in vitro by combination-index analysis in SK-N-BE(2c) (neuroblastoma) and UVW/NAT (NAT-transfected glioma) cells. Three treatment schedules were evaluated: topotecan administered 24 h before, 24 h after, or simultaneously with PJ34. Combinations of PJ34 and 131I-MIBG and of PJ34 and 131I-MIBG/topotecan were also assessed using similar scheduling. In vivo efficacy was measured by growth delay of tumor xenografts. We also assessed DNA damage by γH2A.X assay, cell cycle progression by fluorescence-activated cell sorting analysis, and PARP-1 activity in treated cells. Results: In vitro, only simultaneous administration of topotecan and PJ34 or PJ34 and 131I-MIBG induced supraadditive toxicity in both cell lines. All scheduled combinations of PJ34 and 131I-MIBG/topotecan induced supraadditive toxicity and increased DNA damage in SK-N-BE(2c) cells, but only simultaneous administration induced enhanced efficacy in UVW/NAT cells. The PJ34 and 131I-MIBG/ topotecan combination treatment induced G2 arrest in all cell lines, regardless of the schedule of delivery. In vivo, simultaneous administration of PJ34 and 131I-MIBG/topotecan significantly delayed the growth of SK-N-BE(2c) and UVW/NAT xenografts, compared with 131I-MIBG/topotecan therapy. Conclusion: The antitumor efficacy of topotecan, 131I-MIBG, and 131I-MIBG/topotecan combination treatment was increased by PARP-1 inhibition in vitro and in vivo. Copyright © 2012 by the Society of Nuclear Medicine, Inc.


Nicol A.,Southern General Hospital | Krishnadas R.,University of Glasgow | Champion S.,University of Glasgow | Tamagnan G.,Institute for Neurodegenerative Disorders | And 4 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2012

Purpose 123I-labelled mZIENT (2β-carbomethoxy-3β- (3′- ((Z)-2-iodoethenyl)phenyl)nortropane) has been developed as a radioligand for the serotonin transporter. The aim of this preliminary study was to assess its whole-body biodistribution in humans and estimate dosimetry. Methods Three healthy controls and three patients receiving selective serotonin reuptake inhibitor (SSRI) therapy for depression were included (two men, four women, age range 41-56 years). Whole-body imaging, brain SPECT imaging and blood and urine sampling were performed. Whole-body images were analysed using regions of interest (ROIs), time-activity curves were derived using compartmental analysis and dosimetry estimated using OLINDA software. Brain ROI analysis was performed to obtain specific-tononspecific binding ratios in the midbrain, thalamus and striatum. Results Initial high uptake in the lungs decreased in later images. Lower uptake was seen in the brain, liver and intestines. Excretion was primarily through the urinary system. The effective dose was estimated to be of the order of 0.03 mSv/MBq. The organ receiving the highest absorbed dose was the lower large intestine wall. Uptake in the brain was consistent with the known SERT distribution with higher specific-to- nonspecific binding in the midbrain, thalamus and striatum in healthy controls compared with patients receiving SSRI therapy. Conclusion 123I-mZIENT may be a promising radioligand for imaging the serotonin transporters in humans with acceptable dosimetry. © Springer-Verlag 2012.


Pimlott S.L.,West of Scotland Radionuclide Dispensary | Sutherland A.,University of Glasgow
Chemical Society Reviews | Year: 2011

The development of positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging continues to grow due to the ability of these techniques to allow the non-invasive in vivo visualisation of biological processes at the molecular and cellular levels. As well as finding application for the diagnosis of disease, these techniques have also been used in the drug discovery process. Crucial to the growth of these techniques is the continued development of molecular probes that can bind to the target biological receptor with high selectivity. This tutorial review describes the use of PET and SPECT for molecular imaging and highlights key strategies for the development of molecular probes for the imaging of both cancer and neurological diseases. © 2011 The Royal Society of Chemistry.


Colloby S.J.,Vitality | Perry E.K.,Vitality | Pakrasi S.,Vitality | Pimlott S.L.,West of Scotland Radionuclide Dispensary | And 4 more authors.
American Journal of Geriatric Psychiatry | Year: 2010

OBJECTIVE: To investigate normalized I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) single photon emission computed tomography (SPECT) imaging, a marker for the α4β2 nicotinic receptor, as a predictor of cognitive progression in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). METHODS: Thirty-one patients with dementia (16 patients with AD and 15 patients with DLB) underwent I-5IA-85380 SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM2), which involved spatial preprocessing of scans to standard Montreal Neurological Institute space and intensity normalization of each image to its mean global brain activity. RESULTS: Regression analysis revealed that reduced normalized I-5IA-85380 uptake in left superior, middle, and inferior frontal gyri and prepost central and anterior cingulate regions significantly correlated with decline in executive function in a pooled group comprising AD and DLB. CONCLUSION: The findings, although preliminary, suggest that the cholinergic system may be more involved in neurodegenerative processes affecting some cognitive processes more than others, as such, this procedure may be useful for increased understanding of the pathophysiological mechanisms responsible for neurodegeneration. © 2009 American Association for Geriatric Psychiatry.


Colloby S.J.,Vitality | Firbank M.J.,Vitality | Pakrasi S.,Vitality | Perry E.K.,Vitality | And 5 more authors.
Neurobiology of Aging | Year: 2011

Objective: To investigate differences in distribution of α4β2 subtypes of nicotinic acetylcholine receptors (nAChRs) using the ligand 123I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) and single photon emission computed tomography (SPECT) in subjects with vascular dementia and age-matched controls. 123I-5IA-85380 binding was compared to corresponding regional cerebral blood flow (rCBF) changes in the same subjects. Methods: Thirty subjects (14 vascular dementia and 16 controls) underwent 123I-5IA-85380 and rCBF (99mTc-exametazime) SPECT scanning. Image analysis was performed on voxel basis using statistical parametric mapping (SPM2). Results: Compared to controls, reductions in relative 123I-5IA-85380 uptake were identified in dorsal thalamus and right caudate in vascular dementia. Increase in scaled 123I-5IA-85380 uptake in cuneus was also demonstrated in vascular dementia relative to controls. Perfusion deficits in anterior cingulate were apparent in the patient group and did not appear to be associated with 123I-5IA-85380 changes. Conclusions: Reduced 123I-5IA-85380 uptake in vascular dementia was confined to sub-cortical regions, unlike the cortical reductions previously described in Alzheimer's disease. Elevation of normalised 123I-5IA-85380 uptake in cuneus in vascular dementia could be a compensatory response to reduced cholinergic activity in dorsal thalamus. © 2009 Elsevier Inc.


Cant A.A.,University of Glasgow | Bhalla R.,Grove Center | Pimlott S.L.,West of Scotland Radionuclide Dispensary | Sutherland A.,University of Glasgow
Chemical Communications | Year: 2012

A fast and efficient nickel-catalysed iodination reaction of aryl and heteroaryl bromides has been developed. The transformation was found to be general for a wide range of substrates and was used for the synthesis of iodo-PK11195, an imaging agent of Alzheimer's disease and iniparib, a compound used in the treatment of breast cancer. © 2012 The Royal Society of Chemistry.


McCuskey A.G.,University of Strathclyde | Mairs R.J.,University of Glasgow | Sorensen A.,University of Strathclyde | Robson T.,Queen's University of Belfast | And 5 more authors.
Radiation Research | Year: 2013

The use of radiation-inducible promoters to drive transgene expression offers the possibility of temporal and spatial regulation of gene activation. This study assessed the potential of one such promoter element, p21 WAF1/CIP1 (WAF1), to drive expression of the noradrenaline transporter (NAT) gene, which conveys sensitivity to radioiodinated meta-iodobenzylguanidine (MIBG). An expression vector containing NAT under the control of the radiation-inducible WAF1 promoter (pWAF/NAT) was produced. The non-NAT expressing cell lines UVW (glioma) and HCT116 (colorectal cancer) were transfected with this construct to assess radiation-controlled WAF1 activation of the NAT gene. Transfection of UVW and HCT cells with pWAF/NAT conferred upon them the ability to accumulate [131I]MIBG, which led to increased sensitivity to the radiopharmaceutical. Pretreatment of transfected cells with γ radiation or the radiopharmaceuticals [123I]MIBG or [ 131I]MIBG induced dose- and time-dependent increases in subsequent [131I]MIBG uptake and led to enhanced efficacy of [ 131I]MIBG-mediated cell kill. Gene therapy using WAF1-driven expression of NAT has the potential to expand the use of this therapeutic modality to tumors that lack a radio-targetable feature. © 2013 by Radiation Research Society.


PubMed | University of Glasgow, West of Scotland Radionuclide Dispensary, Western Infirmary and Southern General Hospital
Type: | Journal: Brain, behavior, and immunity | Year: 2015

Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-), would be associated with greater 5-HTT availability, and that TNF- inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF- correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [(123)I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF- concentrations on BDI scores. Treatment with etanercept for 6-8weeks was associated with a significant reduction in 5-HTT availability (Z=2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF- and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF- and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression.


PubMed | West of Scotland Radionuclide Dispensary
Type: Journal Article | Journal: Chemical Society reviews | Year: 2010

The development of positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging continues to grow due to the ability of these techniques to allow the non-invasive in vivo visualisation of biological processes at the molecular and cellular levels. As well as finding application for the diagnosis of disease, these techniques have also been used in the drug discovery process. Crucial to the growth of these techniques is the continued development of molecular probes that can bind to the target biological receptor with high selectivity. This tutorial review describes the use of PET and SPECT for molecular imaging and highlights key strategies for the development of molecular probes for the imaging of both cancer and neurological diseases.

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