27 results on '"Barry, Simon T."'
Search Results
2. Crystal Structure of Human Thymidine Phosphorylase in Complex with a Small Molecule Inhibitor
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Norman, Richard A., Barry, Simon T., Bate, Michael, Breed, Jason, Colls, Jeremy G., Ernill, Richard J., Luke, Richard W.A., Minshull, Claire A., McAlister, Mark S.B., McCall, Eileen J., McMiken, Helen H.J., Paterson, Dougie S., Timms, David, Tucker, Julie A., and Pauptit, Richard A.
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THYMIDINE , *PHOSPHORYLASES , *GROWTH factors , *DRUG therapy - Abstract
Human thymidine phosphorylase (HTP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), is overexpressed in certain solid tumors where it is linked to poor prognosis. HTP expression is utilized for certain chemotherapeutic strategies and is also thought to play a role in tumor angiogenesis. We determined the structure of HTP bound to the small molecule inhibitor 5-chloro-6-[1-(2-iminopyrrolidinyl) methyl] uracil hydrochloride (TPI). The inhibitor appears to mimic the substrate transition state, which may help explain the potency of this inhibitor and the catalytic mechanism of pyrimidine nucleotide phosphorylases (PYNPs). Further, we have confirmed the validity of the HTP structure as a template for structure-based drug design by predicting binding affinities for TPI and other known HTP inhibitors using in silico docking techniques. This work provides the first structural insight into the binding mode of any inhibitor to this important drug target and forms the basis for designing novel inhibitors for use in anticancer therapy. [Copyright &y& Elsevier]
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- 2004
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3. Capivasertib combines with docetaxel to enhance anti-tumour activity through inhibition of AKT-mediated survival mechanisms in prostate cancer.
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Eberlein, Cath, Williamson, Stuart C., Hopcroft, Lorna, Ros, Susana, Moss, Jennifer I., Kerr, James, van Weerden, Wytske M., de Bruin, Elza C., Dunn, Shanade, Willis, Brandon, Ross, Sarah J., Rooney, Claire, and Barry, Simon T.
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Background/objective: To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null and WT prostate tumours. Methods: Mechanisms associated with docetaxel capivasertib treatment activity in prostate cancer were examined using a panel of in vivo tumour models and cell lines. Results: Combining docetaxel and capivasertib had increased activity in PTEN null and WT prostate tumour models in vivo. In vitro short-term docetaxel treatment caused cell cycle arrest in the majority of cells. However, a sub-population of docetaxel-persister cells did not undergo G2/M arrest but upregulated phosphorylation of PI3K/AKT pathway effectors GSK3β, p70S6K, 4E-BP1, but to a lesser extent AKT. In vivo acute docetaxel treatment induced p70S6K and 4E-BP1 phosphorylation. Treating PTEN null and WT docetaxel-persister cells with capivasertib reduced PI3K/AKT pathway activation and cell cycle progression. In vitro and in vivo it reduced proliferation and increased apoptosis or DNA damage though effects were more marked in PTEN null cells. Docetaxel-persister cells were partly reliant on GSK3β as a GSK3β inhibitor AZD2858 reversed capivasertib-induced apoptosis and DNA damage. Conclusion: Capivasertib can enhance anti-tumour effects of docetaxel by targeting residual docetaxel-persister cells, independent of PTEN status, to induce apoptosis and DNA damage in part through GSK3β. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Perfusion Air Culture of Precision-Cut Tumor Slices: An Ex Vivo System to Evaluate Individual Drug Response under Controlled Culture Conditions.
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Dong, Meng, Böpple, Kathrin, Thiel, Julia, Winkler, Bernd, Liang, Chunguang, Schueler, Julia, Davies, Emma J., Barry, Simon T., Metsalu, Tauno, Mürdter, Thomas E., Sauer, Georg, Ott, German, Schwab, Matthias, and Aulitzky, Walter E.
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PROGRAMMED cell death 1 receptors , *PERFUSION , *OVARIAN tumors , *TUMOR microenvironment , *DNA damage , *ANIMAL models in research - Abstract
Precision-cut tumor slices (PCTS) maintain tissue heterogeneity concerning different cell types and preserve the tumor microenvironment (TME). Typically, PCTS are cultured statically on a filter support at an air–liquid interface, which gives rise to intra-slice gradients during culture. To overcome this problem, we developed a perfusion air culture (PAC) system that can provide a continuous and controlled oxygen medium, and drug supply. This makes it an adaptable ex vivo system for evaluating drug responses in a tissue-specific microenvironment. PCTS from mouse xenografts (MCF-7, H1437) and primary human ovarian tumors (primary OV) cultured in the PAC system maintained the morphology, proliferation, and TME for more than 7 days, and no intra-slice gradients were observed. Cultured PCTS were analyzed for DNA damage, apoptosis, and transcriptional biomarkers for the cellular stress response. For the primary OV slices, cisplatin treatment induced a diverse increase in the cleavage of caspase-3 and PD-L1 expression, indicating a heterogeneous response to drug treatment between patients. Immune cells were preserved throughout the culturing period, indicating that immune therapy can be analyzed. The novel PAC system is suitable for assessing individual drug responses and can thus be used as a preclinical model to predict in vivo therapy responses. [ABSTRACT FROM AUTHOR]
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- 2023
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5. VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status.
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Bizzaro, Francesca, Fuso Nerini, Ilaria, Taylor, Molly A., Anastasia, Alessia, Russo, Massimo, Damia, Giovanna, Guffanti, Federica, Guana, Francesca, Ostano, Paola, Minoli, Lucia, Hattersley, Maureen M., Arnold, Stephanie, Ramos-Montoya, Antonio, Williamson, Stuart C., Galbiati, Alessandro, Urosevic, Jelena, Leo, Elisabetta, Cavallaro, Ugo, Ghilardi, Carmen, and Barry, Simon T.
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POLY(ADP-ribose) polymerase , *OVARIAN cancer , *BRCA genes , *CELL receptors , *TUMOR microenvironment , *RECOMBINANT DNA - Abstract
Poly ADP-ribose polymerase inhibitors (PARPi) have transformed ovarian cancer (OC) treatment, primarily for tumours deficient in homologous recombination repair. Combining VEGF-signalling inhibitors with PARPi has enhanced clinical benefit in OC. To study drivers of efficacy when combining PARP inhibition and VEGF-signalling, a cohort of patient-derived ovarian cancer xenografts (OC-PDXs), representative of the molecular characteristics and drug sensitivity of patient tumours, were treated with the PARPi olaparib and the VEGFR inhibitor cediranib at clinically relevant doses. The combination showed broad anti-tumour activity, reducing growth of all OC-PDXs, regardless of the homologous recombination repair (HRR) mutational status, with greater additive combination benefit in tumours poorly sensitive to platinum and olaparib. In orthotopic models, the combined treatment reduced tumour dissemination in the peritoneal cavity and prolonged survival. Enhanced combination benefit was independent of tumour cell expression of receptor tyrosine kinases targeted by cediranib, and not associated with change in expression of genes associated with DNA repair machinery. However, the combination of cediranib with olaparib was effective in reducing tumour vasculature in all the OC-PDXs. Collectively our data suggest that olaparib and cediranib act through complementary mechanisms affecting tumour cells and tumour microenvironment, respectively. This detailed analysis of the combined effect of VEGF-signalling and PARP inhibitors in OC-PDXs suggest that despite broad activity, there is no dominant common mechanistic inter-dependency driving therapeutic benefit. [ABSTRACT FROM AUTHOR]
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- 2021
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6. Correction: Brüning-Richardson et al. GSK-3 Inhibition Is Cytotoxic in Glioma Stem Cells through Centrosome Destabilization and Enhances the Effect of Radiotherapy in Orthotopic Models. Cancers 2021, 13 , 5939.
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Brüning-Richardson, Anke, Shaw, Gary C., Tams, Daniel, Brend, Tim, Sanganee, Hitesh, Barry, Simon T., Hamm, Gregory, Goodwin, Richard J. A., Swales, John G., King, Henry, Steele, Lynette, Morton, Ruth, Widyadari, Anastasia, Ward, Thomas A., Esteves, Filomena, Boissinot, Marjorie, Mavria, Georgia, Droop, Alastair, Lawler, Sean E., and Short, Susan C.
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GLIOMAS , *STEM cells , *TRANSFERASES - Published
- 2022
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7. Evaluation of dynamic contrast-enhanced MRI biomarkers for stratified cancer medicine: How do permeability and perfusion vary between human tumours?
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Little, Ross A., Barjat, Hervé, Hare, Jennifer I., Jenner, Mary, Watson, Yvonne, Cheung, Susan, Holliday, Katherine, Zhang, Weijuan, O'Connor, James P.B., Barry, Simon T., Puri, Sanyogitta, Parker, Geoffrey J.M., and Waterton, John C.
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MAGNETIC resonance imaging , *TUMOR diagnosis , *BAYESIAN analysis , *DRUG delivery systems , *DOSAGE forms of drugs , *PERMEABILITY measurement - Abstract
Background Solid tumours exhibit enhanced vessel permeability and fenestrated endothelium to varying degree, but it is unknown how this varies in patients between and within tumour types. Dynamic contrast-enhanced (DCE) MRI provides a measure of perfusion and permeability, the transfer constant K trans , which could be employed for such comparisons in patients. Aim To test the hypothesis that different tumour types exhibit systematically different K trans . Materials and methods DCE-MRI data were retrieved from 342 solid tumours in 230 patients. These data were from 18 previous studies, each of which had had a different analysis protocol. All data were reanalysed using a standardised workflow using an extended Tofts model. A model of the posterior density of median K trans was built assuming a log-normal distribution and fitting a simple Bayesian hierarchical model. Results 12 histological tumour types were included. In glioma, median K trans was 0.016 min − 1 and for non-glioma tumours, median K trans ranged from 0.10 (cervical) to 0.21 min − 1 (prostate metastatic to bone). The geometric mean (95% CI) across all the non-glioma tumours was 0.15 (0.05, 0.45) min − 1 . There was insufficient separation between the posterior densities to be able to predict the K trans value of a tumour given the tumour type, except that the median K trans for gliomas was below 0.05 min − 1 with 80% probability, and median K trans measurements for the remaining tumour types were between 0.05 and 0.4 min − 1 with 80% probability. Conclusion With the exception of glioma, our hypothesis that different tumour types exhibit different K trans was not supported. Studies in which tumour permeability is believed to affect outcome should not simply seek tumour types thought to exhibit high permeability. Instead, K trans is an idiopathic parameter, and, where permeability is important, K trans should be measured in each tumour to personalise that treatment. [ABSTRACT FROM AUTHOR]
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- 2018
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8. Developing PreDICT – a fully integrated data platform for preclinical in vivo data: learning from experience.
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Jones, Rhys D.o., Cooke, Marie, Hinchliffe, James, Morley, Justin, and Barry, Simon T.
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THERAPEUTICS , *PHARMACOKINETICS , *DRUG efficacy , *SEQUENTIAL analysis , *PHARMACODYNAMICS - Abstract
In vivo models have been crucial for developing our understanding of key processes associated with human disease and developing novel therapeutics. These in vivo studies are becoming increasingly complex, requiring long-term efficacy data and additional supportive datasets such as pharmacokinetic profiles and analysis of multiple biomarkers of pharmacodynamic response and efficacy. Moreover, a new agent will be investigated in many different models and often in combination with other drugs. Despite advances across the industry integrating and analysing complex datasets, management of in vivo data remains an ongoing challenge across the industry. Here, we describe a project that has successfully delivered a working solution to integrate pharmacokinetic, biomarker and efficacy data, independent of therapy area. [ABSTRACT FROM AUTHOR]
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- 2017
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9. Tumour regression and improved gastrointestinal tolerability from controlled release of SN-38 from novel polyoxazoline-modified dendrimers.
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England, Richard M., Hare, Jennifer I., Barnes, Jennifer, Wilson, Joanne, Smith, Aaron, Strittmatter, Nicole, Kemmitt, Paul D., Waring, Michael J., Barry, Simon T., Alexander, Cameron, and Ashford, Marianne B.
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OXAZOLINE , *DENDRIMERS , *COLON cancer treatment , *IRINOTECAN , *DRUG delivery systems - Abstract
Irinotecan is used clinically for the treatment of colorectal cancer; however, its utility is limited by its narrow therapeutic index. We describe the use of a generation 5 l -lysine dendrimer that has been part-modified with a polyoxazoline as a drug delivery vehicle for improving the therapeutic index of SN-38, the active metabolite of irinotecan. By conjugating SN-38 to the dendrimer via different linker technologies we sought to vary the release rate of the drug to generate diverse pharmacokinetic profiles. Three conjugates with plasma release half-lives of 2.5 h, 21 h, and 72 h were tested for efficacy and toxicity using a mouse SW620 xenograft model. In this model, the linker with a plasma release half-life of 21 h achieved sustained SN-38 exposure in blood, above the target concentration. Control over the release rate of the drug from the linker, combined with prolonged circulation of the dendrimer, enabled administration of an efficacious dose of SN-38, achieving significant regression of the SW620 tumours. The conjugates with 2.5 and 72 h release half-lives did not achieve an anti-tumour effect. Intraperitoneal dosing of the clinically used prodrug irinotecan produces high initial and local concentrations of SN-38, which are associated with gastrointestinal toxicity. Administration of the 21 h release dendrimer conjugate did not produce a high initial C max of SN-38. Consequently, a marked reduction in gastrointestinal toxicity was observed relative to irinotecan treatment. Additional studies investigating the dose concentrations and dose scheduling showed that a weekly dosing schedule of 4 mg SN-38/kg was the most efficacious regimen. After 4 doses at weekly intervals, the survival period of the mice extended beyond 70 days following the final dose. These extensive studies have allowed us to identify a linker, dose and dosing regimen for SN-38 conjugated to polyoxazoline-modified dendrimer that maximised efficacy and minimised adverse side effects. [ABSTRACT FROM AUTHOR]
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- 2017
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10. Challenges and strategies in anti-cancer nanomedicine development: An industry perspective.
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Hare, Jennifer I., Lammers, Twan, Ashford, Marianne B., Puri, Sanyogitta, Storm, Gert, and Barry, Simon T.
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ANTINEOPLASTIC agents , *NANOMEDICINE , *DRUG development , *PHARMACEUTICAL industry , *DRUG delivery systems , *DRUG design - Abstract
Successfully translating anti-cancer nanomedicines from pre-clinical proof of concept to demonstration of therapeutic value in the clinic is challenging. Having made significant advances with drug delivery technologies, we must learn from other areas of oncology drug development, where patient stratification and target-driven design have improved patient outcomes. We should evolve our nanomedicine development strategies to build the patient and disease into the line of sight from the outset. The success of small molecule targeted therapies has been significantly improved by employing a specific decision-making framework, such as AstraZeneca's 5R principle: right target/efficacy, right tissue/exposure, right safety, right patient, and right commercial potential. With appropriate investment and collaboration to generate a platform of evidence supporting the end clinical application, a similar framework can be established for enhancing nanomedicine translation and performance. Building informative data packages to answer these questions requires the following: (I) an improved understanding of the heterogeneity of clinical cancers and of the biological factors influencing the behaviour of nanomedicines in patient tumours; (II) a transition from formulation-driven research to disease-driven development; (III) the implementation of more relevant animal models and testing protocols; and (IV) the pre-selection of the patients most likely to respond to nanomedicine therapies. These challenges must be overcome to improve (the cost-effectiveness of) nanomedicine development and translation, and they are key to establishing superior therapies for patients. [ABSTRACT FROM AUTHOR]
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- 2017
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11. Modulation of FAK and Src adhesion signaling occurs independently of adhesion complex composition.
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Horton, Edward R., Humphries, Jonathan D., Stutchbury, Ben, Jacquemet, Guillaume, Ballestrem, Christoph, Barry, Simon T., and Humphries, Martin J.
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FOCAL adhesion kinase , *SRC gene , *INTEGRINS , *CELL adhesion , *PHOSPHOTYROSINE , *CELL migration , *CELLULAR signal transduction - Abstract
Integrin adhesion complexes (IACs) form mechanochemical connections between the extracellular matrix and actin cytoskeleton and mediate phenotypic responses via posttranslational modifications. Here, we investigate the modularity and robustness of the IAC network to pharmacological perturbation of the key IAC signaling components focal adhesion kinase (FAK) and Src. FAK inhibition using AZ13256675 blocked FAKY397 phosphorylation but did not alter IAC composition, as reported by mass spectrometry. IAC composition was also insensitive to Src inhibition using AZD0530 alone or in combination with FAK inhibition. In contrast, kinase inhibition substantially reduced phosphorylation within IACs, cell migration and proliferation. Furthermore using fluorescence recovery after photobleaching, we found that FAK inhibition increased the exchange rate of a phosphotyrosine (pY) reporter (dSH2) at IACs. These data demonstrate that kinase-dependent signal propagation through IACs is independent of gross changes in IAC composition. Together, these findings demonstrate a general separation between the composition of IACs and their ability to relay pY-dependent signals. [ABSTRACT FROM AUTHOR]
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- 2016
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12. Modelling the tumour microenvironment in long-term microencapsulated 3D co-cultures recapitulates phenotypic features of disease progression.
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Estrada, Marta F., Rebelo, Sofia P., Davies, Emma J., Pinto, Marta T., Pereira, Hugo, Santo, Vítor E., Smalley, Matthew J., Barry, Simon T., Gualda, Emilio J., Alves, Paula M., Anderson, Elizabeth, and Brito, Catarina
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MICROENCAPSULATION , *BIOACTIVE compounds , *TISSUE scaffolds , *CANCER invasiveness , *HUMAN phenotype , *ALGINATES - Abstract
3D cell tumour models are generated mainly in non-scalable culture systems, using bioactive scaffolds. Many of these models fail to reflect the complex tumour microenvironment and do not allow long-term monitoring of tumour progression. To overcome these limitations, we have combined alginate microencapsulation with agitation-based culture systems, to recapitulate and monitor key aspects of the tumour microenvironment and disease progression. Aggregates of MCF-7 breast cancer cells were microencapsulated in alginate, either alone or in combination with human fibroblasts, then cultured for 15 days. In co-cultures, the fibroblasts arranged themselves around the tumour aggregates creating distinct epithelial and stromal compartments. The presence of fibroblasts resulted in secretion of pro-inflammatory cytokines and deposition of collagen in the stromal compartment. Tumour cells established cell–cell contacts and polarised around small lumina in the interior of the aggregates. Over the culture period, there was a reduction in oestrogen receptor and membranous E-cadherin alongside loss of cell polarity, increased collective cell migration and enhanced angiogenic potential in co-cultures. These phenotypic alterations, typical of advanced stages of cancer, were not observed in the mono-cultures of MCF-7 cells. The proposed model system constitutes a new tool to study tumour-stroma crosstalk, disease progression and drug resistance mechanisms. [ABSTRACT FROM AUTHOR]
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- 2016
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13. PDGFR Inhibition Results in Pericyte Depletion and Hemorrhage into the Corpus Luteum of the Rat Ovary.
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Hall, Anthony P., Ashton, Susan, Horner, Judith, Wilson, Zena, Reens, Jaimini, Richmond, Graham H. P., Barry, Simon T., and Wedge, Steve R.
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PLATELET-derived growth factor receptors , *PERICYTES , *VASCULAR endothelial growth factor receptors , *HEMORRHAGE , *CORPUS luteum , *LABORATORY rats - Abstract
The growth plate, ovary, adrenal gland, and rodent incisor tooth are sentinel organs for antiangiogenic effects since they respond reliably, quantitatively, and sensitively to inhibition of the vascular endothelial growth factor receptor (VEGFR). Here we report that treatment of rats with platelet-derived growth factor receptor beta (PDGFRβ) inhibitors that target pericytes results in severe ovarian hemorrhage with degeneration and eventual rupture of the corpus luteum. Evaluation of the growth plate, adrenal gland, and incisor tooth that are typical target organs for antiangiogenic treatment in the rodent revealed no abnormalities. Histologically, the changes in the ovary were characterized by sinusoidal dilatation, increased vessel fragility, and hemorrhage into the corpus luteum. Immunocytochemical staining of vessels with alpha smooth muscle actin and CD31 that recognize pericytes and vascular endothelium, respectively, demonstrated that this effect was due to selective pericyte deficiency within corpora lutea. Further experiments in which rats were treated concurrently with both PDGFRβ and VEGFR inhibitors ablated the hemorrhagic response, resulting instead in corpus luteum necrosis. These changes are consistent with the notion that selective pericyte loss in the primitive capillary network resulted in increased vessel fragility and hemorrhage, whereas concomitant VEGFR inhibition resulted in vessel regression and reduced vascular perfusion that restricted development of the hemorrhagic vessels. These results also highlight the utility of the rodent ovary to respond differentially to VEGFR and PDGFR inhibitors, which may provide useful information during routine safety assessment for determining target organ toxicity. [ABSTRACT FROM AUTHOR]
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- 2016
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14. High Efficacy of Combination Therapy Using PI3K/AKT Inhibitors with Androgen Deprivation in Prostate Cancer Preclinical Models.
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Marques, Rute B., Aghai, Ashraf, de Ridder, Corrina M.A., Stuurman, Debra, Hoeben, Sander, Boer, Agnes, Ellston, Rebecca P., Barry, Simon T., Davies, Barry R., Trapman, Jan, and van Weerden, Wytske M.
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PROSTATE cancer treatment , *ANDROGEN receptors , *TUMOR growth , *PROSTATE cancer patients , *PHOSPHATASES - Abstract
Background The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT pathway is frequently activated during prostate cancer (PCa) progression through loss or mutation of the phosphatase and tensin homolog (PTEN) gene. Following the androgen receptor (AR) pathway, it is the second major driver of PCa growth. Objective To assess efficacy of novel PI3K/AKT-targeted therapies in PCa models, as a single agent and in combination with androgen deprivation. Design, setting, and participants Twelve human PCa cell lines were tested in vitro for sensitivity to the AKT inhibitor AZD5363 and the PI3K beta/delta inhibitor AZD8186. The combination of AZD5363 and AZD8186 with castration was evaluated in vivo in PTEN-negative versus PTEN-positive patient-derived xenografts. Tumors and plasma were collected for biomarker analysis. Outcome measurements and statistical analysis In vitro growth inhibition was determined by methylthiazolyldiphenyl-tetrazolium bromide assay. In vivo efficacy was monitored by caliper measurements of subcutaneous tumor volume. PI3K/AKT and AR pathway activity was analyzed by Western blot, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction. Results and limitations AZD5363 and AZD8186 inhibited in vitro growth of 10 of 12 and 7 of 12 PCa cell lines, respectively, with increased sensitivity under androgen depletion. In vivo, AZD5363 and AZD8186 as single agents significantly inhibited growth of PTEN-negative PC346C xenografts compared to placebo by 60% and 66%, respectively. Importantly, combination of either agent with castration resulted in long-lasting tumor regression, which persisted after treatment cessation. Expression of AR-target genes kallikrein-related peptidase 3 ( KLK3 , also known as PSA ); transmembrane protease, serine 2 ( TMPRSS2 ); and FK506 binding protein 5 ( FKBP5 ) was upregulated after PI3K/AKT inhibition. Neither compound inhibited tumor growth in the PTEN-positive PC310 model. Conclusions Combination with hormonal therapy improved efficacy of PI3K/AKT-targeted agents in PTEN-negative PCa models. Upregulation of AR-target genes upon PI3K/AKT inhibition suggests a compensatory crosstalk between the PI3K–AR pathways. These data strongly advocate for further clinical evaluation. Patient summary Inactivation of the PTEN gene is a common event promoting prostate cancer (PCa) progression. This preclinical study illustrates the potent anticancer activity of novel PTEN-targeted drugs on PCa models, particularly in combination with hormonal therapy. [ABSTRACT FROM AUTHOR]
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- 2015
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15. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited.
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Boulter, Luke, Guest, Rachel V., Kendall, Timothy J., Wilson, David H., Wojtacha, Davina, Robson, Andrew J., Ridgway, Rachel A., Samuel, Kay, Van Rooijen, Nico, Barry, Simon T., Wigmore, Stephen J., Sansom, Owen J., and Forbes, Stuart J.
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WNT genes , *PROTO-oncogenes , *CHOLANGIOCARCINOMA , *BILE duct diseases , *PHARMACOLOGY - Abstract
Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficienttransgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC. [ABSTRACT FROM AUTHOR]
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- 2015
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16. Feedback Suppression of PI3Kα Signaling in PTEN-Mutated Tumors Is Relieved by Selective Inhibition of PI3Kβ.
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Schwartz, Sarit, Wongvipat, John, Trigwell, Cath B., Hancox, Urs, Carver, Brett S., Rodrik-Outmezguine, Vanessa, Will, Marie, Yellen, Paige, de Stanchina, Elisa, Baselga, José, Scher, Howard I., Barry, Simon T., Sawyers, Charles L., Chandarlapaty, Sarat, and Rosen, Neal
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CELLULAR signal transduction , *GENETIC mutation , *PHOSPHATIDYLINOSITOL 3-kinases , *PROTEIN-tyrosine kinase inhibitors , *MTOR protein , *CANCER research - Abstract
Summary In PTEN -mutated tumors, we show that PI3Kα activity is suppressed and PI3K signaling is driven by PI3Kβ. A selective inhibitor of PI3Kβ inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3Kβ only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3Kα and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3Kα and PI3Kβ. In PTEN -deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions. [ABSTRACT FROM AUTHOR]
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- 2015
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17. Mechanisms that influence tumour response to VEGF-pathway inhibitors.
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Smith, Neil R., Wedge, Stephen R., Pommier, Aurelien, and Barry, Simon T.
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VASCULAR endothelial growth factors , *PROTEIN kinase inhibitors , *TUMOR blood vessels , *NEOVASCULARIZATION , *CELLULAR signal transduction , *SMALL molecules - Abstract
There has been significant investment in developing novel therapies to target solid tumour vasculature. Different technical approaches have been utilized with the aim of inhibiting tumour angiogenesis or compromising the function or stability of pre-existing tumour blood vessels. The vascular endothelial growth factor (VEGF) signalling axis remains the most widely studied, with biological and small-molecule therapeutics now registered for clinical use. However, despite these successes, the activity of these agents is not as widespread as was first postulated. The present review discusses the clinical successes of the VEGF inhibitors, the factors that may limit their utility, and the potential opportunities to maximize benefit from treatment with these agents in the future. [ABSTRACT FROM AUTHOR]
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- 2014
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18. Model-based drug discovery: implementation and impact.
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Visser, Sandra A.G., Aurell, Malin, Jones, Rhys D.O., Schuck, Virna J.A., Egnell, Ann-Charlotte, Peters, Sheila A., Brynne, Lena, Yates, James W.T., Jansson-Löfmark, Rasmus, Tan, Beesan, Cooke, Marie, Barry, Simon T., Hughes, Andrew, and Bredberg, Ulf
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DRUG development , *PHARMACOLOGY , *QUANTITATIVE research , *DECISION making , *DRUG efficacy , *DRUG prices - Abstract
Highlights: [•] Implementation of quantitative pharmacology strategy to discovery drug projects. [•] Building dedicated preclinical M&S capability. [•] Developing a companywide infrastructure for flexible data management and use. [•] Facilitation of rational decision making, increased efficiency and reduced cycle times and costs. [Copyright &y& Elsevier]
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- 2013
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19. GSK-3 Inhibition Is Cytotoxic in Glioma Stem Cells through Centrosome Destabilization and Enhances the Effect of Radiotherapy in Orthotopic Models.
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Brüning-Richardson, Anke, Shaw, Gary C., Tams, Daniel, Brend, Tim, Sanganee, Hitesh, Barry, Simon T., Hamm, Gregory, Goodwin, Richard J. A., Swales, John G., King, Henry, Steele, Lynette, Morton, Ruth, Widyadari, Anastasia, Ward, Thomas A., Esteves, Filomena, Boissinot, Marjorie, Droop, Alastair, Lawler, Sean E., and Short, Susan C.
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BIOLOGICAL models , *XENOGRAFTS , *ANIMAL experimentation , *GLIOMAS , *RATS , *STEM cells , *TRANSFERASES , *CHROMOSOME abnormalities , *CELL lines , *CELL surface antigens , *CYTOTOXINS , *IMMUNODIAGNOSIS , *CELL death - Abstract
Simple Summary: High-grade gliomas remain difficult-to-treat cancers. Novel treatment options include targeting glycogen synthase kinase 3 (GSK-3) to induce cell death but the mode of drug activity remains unknown and combination with conventional treatment including radiotherapy has not been explored. Here, we describe the effect of targeting GSK-3 with the inhibitor AZD2858 in in vitro and in vivo models of glioma. We established that AZD2858 exposure induces mitotic defects leading to cell death in patient-derived glioma cell lines and tumor growth delay in glioma xenografts. Co-administration also enhanced the effect of radiotherapy. We therefore propose AZD2858 as an adjuvant to radiotherapy in high-grade glioma. Background: Previous data on glycogen synthase kinase 3 (GSK-3) inhibition in cancer models support a cytotoxic effect with selectivity for tumor cells compared to normal tissue but the effect of these inhibitors in glioma has not been widely studied. Here, we investigate their potential as cytotoxics in glioma. Methods: We assessed the effect of pharmacologic GSK-3 inhibition on established (U87, U251) and patient-derived (GBM1, GBM4) glioblastoma (GBM) cell lines using cytotoxicity assays as well as undertaking a detailed investigation of the effect on cell cycle, mitosis, and centrosome biology. We also assessed drug uptake and efficacy of GSK-3 inhibition alone and in combination with radiation in xenograft models. Results: Using the selective GSK-3 inhibitor AZD2858, we demonstrated single agent cytotoxicity in two patient-derived glioma cell lines (GBM1, GBM4) and two established cell lines (U251 and U87) with IC50 in the low micromolar range promoting centrosome disruption, failed mitosis, and S-phase arrest. Glioma xenografts exposed to AZD2858 also showed growth delay compared to untreated controls. Combined treatment with radiation increased the cytotoxic effect of clinical radiation doses in vitro and in orthotopic glioma xenografts. Conclusions: These data suggest that GSK-3 inhibition promotes cell death in glioma through disrupting centrosome function and promoting mitotic failure and that AZD2858 is an effective adjuvant to radiation at clinical doses. [ABSTRACT FROM AUTHOR]
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- 2021
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20. RNA-Seq Differentiates Tumour and Host mRNA Expression Changes Induced by Treatment of Human Tumour Xenografts with the VEGFR Tyrosine Kinase Inhibitor Cediranib.
- Author
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Bradford, James R., Farren, Matthew, Powell, Steve J., Runswick, Sarah, Weston, Susie L., Brown, Helen, Delpuech, Oona, Wappett, Mark, Smith, Neil R., Carr, T. Hedley, Dry, Jonathan R., Gibson, Neil J., and Barry, Simon T.
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TUMOR treatment , *NUCLEOTIDE sequence , *MESSENGER RNA , *GENE expression , *VASCULAR endothelial growth factor receptors , *PROTEIN-tyrosine kinases , *ENZYME inhibitors , *CANCER cell differentiation - Abstract
Pre-clinical models of tumour biology often rely on propagating human tumour cells in a mouse. In order to gain insight into the alignment of these models to human disease segments or investigate the effects of different therapeutics, approaches such as PCR or array based expression profiling are often employed despite suffering from biased transcript coverage, and a requirement for specialist experimental protocols to separate tumour and host signals. Here, we describe a computational strategy to profile transcript expression in both the tumour and host compartments of pre-clinical xenograft models from the same RNA sample using RNA-Seq. Key to this strategy is a species-specific mapping approach that removes the need for manipulation of the RNA population, customised sequencing protocols, or prior knowledge of the species component ratio. The method demonstrates comparable performance to species-specific RT-qPCR and a standard microarray platform, and allowed us to quantify gene expression changes in both the tumour and host tissue following treatment with cediranib, a potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, including the reduction of multiple murine transcripts associated with endothelium or vessels, and an increase in genes associated with the inflammatory response in response to cediranib. In the human compartment, we observed a robust induction of hypoxia genes and a reduction in cell cycle associated transcripts. In conclusion, the study establishes that RNA-Seq can be applied to pre-clinical models to gain deeper understanding of model characteristics and compound mechanism of action, and to identify both tumour and host biomarkers. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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21. Challenges and Key Considerations of the Enhanced Permeability and Retention Effect for Nanomedicine Drug Delivery in Oncology.
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Prabhakar, Uma, Hiroshi Maeda, Jain, Rakesh K., Sevick-Muraca, Eva M., Zamboni, William, Farokhzad, Omid C., Barry, Simon T., Gabizon, Alberto, Grodzinsk, Piotr, and Blakey, David C.
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PERMEABILITY , *NANOMEDICAL research , *NANOBIOTECHNOLOGY , *DRUG delivery systems , *ONCOLOGY research - Abstract
Enhanced permeability of the tumor vasculature allows macromolecules to enter the tumor interstitial space, whereas the suppressed lymphatic filtration allows them to stay there. This phenomenon, enhanced permeability and retention (EPR), has been the basis of nanotechnology platforms to deliver drugs to tumors. However, progress in developing effective drugs using this approach has been hampered by heterogeneity of EPR effect in different tumors and limited experimental data from patients on effectiveness of this mechanism as related to enhanced drug accumulation. This report summarizes the workshop discussions on key issues of the EPR effect and major gaps that need to be addressed to effectively advance nanoparticle-based drug delivery. [ABSTRACT FROM AUTHOR]
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- 2013
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22. Structure–activity relationship of a series of non peptidic RGD integrin antagonists targeting α5β1: Part 2
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Delouvrié, Bénédicte, Al-Kadhimi, Katherine, Arnould, Jean-Claude, Barry, Simon T., Cross, Darren A.E., Didelot, Myriam, Gavine, Paul R., Germain, Hervé, Harris, Craig S., Hughes, Adina M., Jude, David A., Kendrew, Jane, Lambert-van der Brempt, Christine, Lohmann, Jean-Jacques, Ménard, Morgan, Mortlock, Andrew A., Pass, Martin, Rooney, Claire, Vautier, Michel, and Vincent, Jennifer L.
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STRUCTURE-activity relationship in pharmacology , *TARGETED drug delivery , *INTEGRINS , *PEPTIDES , *DRUG synergism , *TYROSINE - Abstract
Abstract: Potent antagonists of the integrin α5β1, which are RGD mimetics built from tyrosine are described. This paper describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the central aromatic core and the amide moiety. [Copyright &y& Elsevier]
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- 2012
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23. Structure–activity relationship of a series of non peptidic RGD integrin antagonists targeting α5β1: Part 1
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Delouvrié, Bénédicte, Al-Kadhimi, Katherine, Arnould, Jean-Claude, Barry, Simon T., Cross, Darren A.E., Didelot, Myriam, Gavine, Paul R., Germain, Hervé, Harris, Craig S., Hughes, Adina M., Jude, David A., Kendrew, Jane, Lambert-van der Brempt, Christine, Lohmann, Jean-Jacques, Ménard, Morgan, Mortlock, Andrew A., Pass, Martin, Rooney, Claire, Vautier, Michel, and Vincent, Jennifer L.
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STRUCTURE-activity relationship in pharmacology , *INTEGRINS , *TARGETED drug delivery , *DRUG synergism , *TYROSINE , *PEPTIDES - Abstract
Abstract: Potent antagonists of the integrin α5β1, which are RGD mimetics built from tyrosine are described. This letter describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the basic group and the linker between the basic group and the phenyl central core. [Copyright &y& Elsevier]
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- 2012
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24. VEGFR1 (Flt1) Regulates Rab4 Recycling to Control Fibronectin Polymerization and Endothelial Vessel Branching.
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Jones, Matthew C., Caswell, Patrick T., Moran-Jones, Kim, Roberts, Marnie, Barry, Simon T., Gampel, Alexandra, Mellor, Harry, and Norman, Jim C.
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FIBRONECTINS , *BLOOD-vessel development , *NEOVASCULARIZATION , *ENDOCYTOSIS , *POLYMERIZATION - Abstract
The cell's main receptor for VEGF, VEGFR2 (Kdr) is one of the most important positive regulators of new blood vessel growth and its downstream signalling is well characterized. By contrast, VEGFR1 (Flt1) and the mechanisms by which this VEGF receptor promotes branching morphogenesis in angiogenesis remain relatively unclear. Here we report that engagement of VEGFR1 activates a Rab4A-dependent pathway that transports αvβ3 integrin from early endosomes to the plasma membrane, and that this is required for VEGF-driven fibronectin polymerization in endothelial cells. Furthermore, VEGFR1 acts to promote endothelial tubule branching in an organotypic model of angiogenesis via a mechanism that requires Rab4A and αvβ3 integrin. We conclude that a recycling pathway regulated by Rab4A is a critical effector of VEGFR1 during branching morphogenesis of the vasculature. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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25. Longitudinal immune characterization of syngeneic tumor models to enable model selection for immune oncology drug discovery.
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Taylor, Molly A., Hughes, Adina M., Walton, Josephine, Coenen-Stass, Anna M. L., Magiera, Lukasz, Mooney, Lorraine, Bell, Sigourney, Staniszewska, Anna D., Sandin, Linda C., Barry, Simon T., Watkins, Amanda, Carnevalli, Larissa S., and Hardaker, Elizabeth L.
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PROTEIN analysis , *FLOW cytometry , *CANCER treatment , *ONCOLOGY , *IMMUNE system - Abstract
Background: The ability to modulate immune-inhibitory pathways using checkpoint blockade antibodies such as αPD-1, αPD-L1, and αCTLA-4 represents a significant breakthrough in cancer therapy in recent years. This has driven interest in identifying small-molecule-immunotherapy combinations to increase the proportion of responses. Murine syngeneic models, which have a functional immune system, represent an essential tool for pre-clinical evaluation of new immunotherapies. However, immune response varies widely between models and the translational relevance of each model is not fully understood, making selection of an appropriate pre-clinical model for drug target validation challenging. Methods: Using flow cytometry, O-link protein analysis, RT-PCR, and RNAseq we have characterized kinetic changes in immune-cell populations over the course of tumor development in commonly used syngeneic models. Results: This longitudinal profiling of syngeneic models enables pharmacodynamic time point selection within each model, dependent on the immune population of interest. Additionally, we have characterized the changes in immune populations in each of these models after treatment with the combination of α-PD-L1 and α-CTLA-4 antibodies, enabling benchmarking to known immune modulating treatments within each model. Conclusions: Taken together, this dataset will provide a framework for characterization and enable the selection of the optimal models for immunotherapy combinations and generate potential biomarkers for clinical evaluation in identifying responders and non-responders to immunotherapy combinations. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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26. PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity.
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Carnevalli, Larissa S., Sinclair, Charles, Taylor, Molly A., Gutierrez, Pablo Morentin, Langdon, Sophie, Coenen-Stass, Anna M. L., Mooney, Lorraine, Hughes, Adina, Jarvis, Laura, Staniszewska, Anna, Crafter, Claire, Sidders, Ben, Hardaker, Elizabeth, Hudson, Kevin, and Barry, Simon T.
- Abstract
PI3K inhibitors with differential selectivity to distinct PI3K isoforms have been tested extensively in clinical trials, largely to target tumor epithelial cells. PI3K signaling also regulates the immune system and inhibition of PI3Kδ modulate the tumor immune microenvironment of pre-clinical mouse tumor models by relieving T-regs-mediated immunosuppression. PI3K inhibitors as a class and PI3Kδ specifically are associated with immune-related side effects. However, the impact of mixed PI3K inhibitors in tumor immunology is under-explored. Here we examine the differential effects of AZD8835, a dual PI3Kα/δ inhibitor, specifically on the tumor immune microenvironment using syngeneic models. Continuous suppression of PI3Kα/δ was not required for anti-tumor activity, as tumor growth inhibition was potentiated by an intermittent dosing/schedule in vivo. Moreover, PI3Kα/δ inhibition delivered strong single agent anti-tumor activity, which was associated with dynamic suppression of T-regs, improved CD8+ T-cell activation and memory in mouse syngeneic tumor models. Strikingly, AZD8835 promoted robust CD8+ T-cell activation dissociated from its effect on T-regs. This was associated with enhancing effector cell viability/function. Together these data reveal novel mechanisms by which PI3Kα/δ inhibitors interact with the immune system and validate the clinical compound AZD8835 as a novel immunoncology drug, independent of effects on tumor cells. These data support further clinical investigation of PI3K pathway inhibitors as immuno-oncology agents. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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27. Capturing complex tumour biology in vitro: histological and molecular characterisation of precision cut slices.
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Davies, Emma J., Dong, Meng, Gutekunst, Matthias, Närhi, Katja, van Zoggel, Hanneke J. A. A., Blom, Sami, Nagaraj, Ashwini, Metsalu, Tauno, Oswald, Eva, Erkens-Schulze, Sigrun, Delgado San Martin, Juan A., Turkki, Riku, Wedge, Stephen R., af Hällström, Taija M., Schueler, Julia, van Weerden, Wytske M., Verschuren, Emmy W., Barry, Simon T., van der Kuip, Heiko, and Hickman, John A.
- Published
- 2015
- Full Text
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