69 results on '"Paul Elvin"'
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2. Estimated Costs of False Laboratory Diagnoses of Tuberculosis in Three Patients
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Jill M. Northrup, Ann C. Miller, Edward Nardell, Sharon Sharnprapai, Sue Etkind, Jeffrey Driscoll, Michael McGarry, Harry W. Taber, Paul Elvin, Noreen L. Qualls, and Christopher R. Braden
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Costs and cost analysis ,DNA fingerprinting ,Mycobacterium tuberculosis ,restriction fragment length polymorphism ,tuberculosis ,United States ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
We estimated direct medical and nonmedical costs associated with a false diagnosis of tuberculosis (TB) caused by laboratory cross-contamination of Mycobacterium tuberculosis cultures in Massachusetts in 1998 and 1999. For three patients who received misdiagnoses of active TB disease on the basis of laboratory cross-contamination, the costs totaled U.S.$32,618. Of the total, 97% was attributed to the public sector (local and state health departments, public health hospital and laboratory, and county and state correctional facilities); 3% to the private sector (physicians, hospitals, and laboratories); and
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- 2002
- Full Text
- View/download PDF
3. Figure S4 from Androgen Receptor Inhibitor Enhances the Antitumor Effect of PARP Inhibitor in Breast Cancer Cells by Modulating DNA Damage Response
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Seock-Ah Im, Mark J. O'Connor, Paul Elvin, Yaewon Yang, Koung Jin Suh, Debora Keunyoung Kim, Kyung-Hun Lee, Seongyeong Kim, Hyemin Jang, and Ahrum Min
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TOPORS expression determined the combined effects of AZD3514 and olaparib
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- 2023
4. Supplementary Figure 4 from Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer
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Yung-Jue Bang, Tae-You Kim, Sae-Won Han, Sang-Hyun Song, Ahrum Min, Young-Kwang Yoon, Hwang-Phill Kim, Paul Elvin, Do-Youn Oh, Seock-Ah Im, and Hyun-Jin Nam
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PDF file - 135K, Treatment of saracatinib in LS174T and SKBR3 cells
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- 2023
5. Supplementary Figure 3 from Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer
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Yung-Jue Bang, Tae-You Kim, Sae-Won Han, Sang-Hyun Song, Ahrum Min, Young-Kwang Yoon, Hwang-Phill Kim, Paul Elvin, Do-Youn Oh, Seock-Ah Im, and Hyun-Jin Nam
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PDF file - 173K, Induction of Bim by saracatinib treatment
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- 2023
6. Supplementary Figure 5 from Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer
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Yung-Jue Bang, Tae-You Kim, Sae-Won Han, Sang-Hyun Song, Ahrum Min, Young-Kwang Yoon, Hwang-Phill Kim, Paul Elvin, Do-Youn Oh, Seock-Ah Im, and Hyun-Jin Nam
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PDF file - 96K, Downregulation of thymidylate synthase (TS) by saracatinib
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- 2023
7. Supplementary Methods from Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer
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Yung-Jue Bang, Tae-You Kim, Sae-Won Han, Sang-Hyun Song, Ahrum Min, Young-Kwang Yoon, Hwang-Phill Kim, Paul Elvin, Do-Youn Oh, Seock-Ah Im, and Hyun-Jin Nam
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PDF file - 103K
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- 2023
8. Data from Androgen Receptor Inhibitor Enhances the Antitumor Effect of PARP Inhibitor in Breast Cancer Cells by Modulating DNA Damage Response
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Seock-Ah Im, Mark J. O'Connor, Paul Elvin, Yaewon Yang, Koung Jin Suh, Debora Keunyoung Kim, Kyung-Hun Lee, Seongyeong Kim, Hyemin Jang, and Ahrum Min
- Abstract
The androgen receptor (AR) is expressed in 60%–70% of breast cancers regardless of estrogen receptor status, and has been proposed as a therapeutic target in breast cancers that retain AR. In this study, the authors aimed to investigate a new treatment strategy using a novel AR inhibitor AZD3514 in breast cancer. AZD3514 alone had a minimal antiproliferative effect on most breast cancer cell lines irrespective of AR expression level, but it downregulated the expressions of DNA damage response (DDR) molecules, including ATM and chk2, which resulted in the accumulation of damaged DNA in some breast cancer cells. Furthermore, AZD3514 enhanced cellular sensitivity to a PARP inhibitor olaparib by blocking the DDR pathway in breast cancer cells. Furthermore, the downregulation of NKX3.1 expression in MDA-MB-468 cells by AZD3514 occurred in parallel with the suppression of ATM–chk2 axis activation, and the suppression of NKX3.1 by AZD3514 was found to result from AZD3514-induced TOPORS upregulation and a resultant increase in NKX3.1 degradation. The study shows posttranslational regulation of NKX3.1 via TOPORS upregulation by AZD3514-induced ATM inactivation–increased olaparib sensitivity in AR-positive and TOPORS-expressing breast cancer cells, and suggests the antitumor effect of AZD3514/olaparib cotreatment is caused by compromised DDR activity in breast cancer cell lines and in a xenograft model. These results provide a rationale for future clinical trials of olaparib/AR inhibitor combination treatment in breast cancer.
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- 2023
9. Supplementary Figure 1 from Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer
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Yung-Jue Bang, Tae-You Kim, Sae-Won Han, Sang-Hyun Song, Ahrum Min, Young-Kwang Yoon, Hwang-Phill Kim, Paul Elvin, Do-Youn Oh, Seock-Ah Im, and Hyun-Jin Nam
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PDF file - 114K, Chemical structures of investigated molecules in this article
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- 2023
10. Supplementary Figure 2 from Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer
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Yung-Jue Bang, Tae-You Kim, Sae-Won Han, Sang-Hyun Song, Ahrum Min, Young-Kwang Yoon, Hwang-Phill Kim, Paul Elvin, Do-Youn Oh, Seock-Ah Im, and Hyun-Jin Nam
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PDF file - 215K, mRNA and protein expression level of integrin �8 in gastric cancer cell lines
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- 2023
11. Supplementary Data from Phase I Safety, Pharmacokinetics, and Inhibition of Src Activity Study of Saracatinib in Patients with Solid Tumors
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Josep Tabernero, Renee Iacona, Alan Swaisland, Paul Elvin, Esther Casado, Paul Hamberg, Duncan I. Jodrell, Herbert I. Hurwitz, Klaas Hoekman, Isabel Chirivella, Erika Martinelli, Andres Cervantes, and José Baselga
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Supplementary Figure S1; Supplementary Appendix.
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- 2023
12. Data from Phase I Safety, Pharmacokinetics, and Inhibition of Src Activity Study of Saracatinib in Patients with Solid Tumors
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Josep Tabernero, Renee Iacona, Alan Swaisland, Paul Elvin, Esther Casado, Paul Hamberg, Duncan I. Jodrell, Herbert I. Hurwitz, Klaas Hoekman, Isabel Chirivella, Erika Martinelli, Andres Cervantes, and José Baselga
- Abstract
Purpose: This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of the oral Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors.Experimental Design: Part A of the study followed a multiple-ascending dose design to establish the maximum tolerated dose (MTD) of saracatinib. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing.Results: In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and Cmax of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ∼40 hours.Conclusions: Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d. Clin Cancer Res; 16(19); 4876–83. ©2010 AACR.
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- 2023
13. Supplementary material from A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers
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Jan H.M. Schellens, James Yates, Gaia Schiavon, Paul Rugman, Vicky Rowlands, Martin Pass, Rhiannon Maudsley, Justin P.O. Lindemann, Peter Lawrence, Andrew Foxley, Paul Elvin, Elza C. de Bruin, Barry R. Davies, Marie Cullberg, Claire Corcoran, S.Y. Amy Cheung, T. Hedley Carr, J. Carl Barrett, Helen Ambrose, Mathew Tall, Michelle D. Garrett, Peter Kabos, Shannon N. Westin, Benoit You, Philippe L. Bedard, Gerald Batist, J. Alejandro Pérez-Fidalgo, Emma J. Dean, and Udai Banerji
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Supplementary methods and results Supplementary Figure 1. Study 1 (NCT01226316) design Supplementary Figure 2. Dose escalation and DLTs in Part A, with MTDs of the continuous, 4/7, and 2/7 schedules being 320, 480, and 640 mg bid, respectively Supplementary Figure 3. Exploratory mutation analyses (ddPCR) in archival tissue and plasma (ctDNA) samples from a breast cancer patient who had progressive disease as best response (Cb cohort) Supplementary Figure 4. A) Tumour growth inhibition in preclinical tumor xenograft models (BT474c, HGC-27, HCC1954 and 786.0) treated with AZD5363 bid po at the indicated doses. B) AZD5363 PD in BT474c tumor xenografts. C) AZD5363 PD at steady state in BT474c xenograft tumors. D) Time course of pPRAS40 and pAkt S473 in BT474c tumor xenograft tissue following the final dose of AZD5363 after 3 weeks' continuous (100 mg/kg bid) or intermittent dosing (130 mg/kg bid 4/7 and 170 mg/kg bid 2/7) Supplementary Figure 5. Glucose (non-fasting/random) values over time after 480 mg single-dose AZD5363 (all dosing schedules) Supplementary Table 1. Percentage change from baseline for PoM biomarkers for 12 evaluable patients Supplementary Table 2. Antibodies and conditions for IHC analysis Supplementary Table 3. ddPCR primers and probes Supplementary Table 4. Tables with results of molecular analyses of Part C patients (PIK3CA and ESR1 mutation status in tissue and ctDNA, PTEN status in archival tissue) Supplementary Table 5. AEs of CTCAE grade {greater than or equal to}3 (irrespective of causality) in Parts A and B (frequency >3% total) and Part C (frequency >5% total)
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- 2023
14. Data from A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers
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Jan H.M. Schellens, James Yates, Gaia Schiavon, Paul Rugman, Vicky Rowlands, Martin Pass, Rhiannon Maudsley, Justin P.O. Lindemann, Peter Lawrence, Andrew Foxley, Paul Elvin, Elza C. de Bruin, Barry R. Davies, Marie Cullberg, Claire Corcoran, S.Y. Amy Cheung, T. Hedley Carr, J. Carl Barrett, Helen Ambrose, Mathew Tall, Michelle D. Garrett, Peter Kabos, Shannon N. Westin, Benoit You, Philippe L. Bedard, Gerald Batist, J. Alejandro Pérez-Fidalgo, Emma J. Dean, and Udai Banerji
- Abstract
Purpose: This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability, and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity.Experimental Design: Patients were aged ≥18 years with World Health Organization (WHO) performance status of 0 to 1. Dose escalation was conducted within separate continuous and intermittent [4 days/week (4/7) or 2 days/week (2/7)] schedules with safety, pharmacokinetic, and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA-mutant breast and gynecologic cancers.Results: MTDs were 320, 480, and 640 mg for continuous (n = 47), 4/7 (n = 21), and 2/7 (n = 22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the prespecified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA-mutant cohort were met.Conclusions: At the recommended phase II dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with PIK3CA-mutant cancers treated with AZD5363. Clin Cancer Res; 24(9); 2050–9. ©2017 AACR.See related commentary by Costa and Bosch, p. 2029
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- 2023
15. Supplementary Table 1 from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas
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François Radvanyi, Jean Paul Thiery, Olivier Delattre, Xavier Sastre-Garau, Bernard Asselain, Brigitte Sigal-Zafrani, Jérôme Couturier, Dominique Stoppa-Lyonnet, Henri Magdelénat, Pierre Pouillart, Claude Nos, Alain Fourquet, Yoann Désille, Carolyn Spraggon, Alexander Graham, Andrew Cassidy, Paul Elvin, Yann de Rycke, Anne Vincent-Salomon, Isabelle Bernard-Pierrot, Nicolas Stransky, and Fabien Reyal
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Supplementary Table 1 from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas
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- 2023
16. Supplementary Figure 2 from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas
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François Radvanyi, Jean Paul Thiery, Olivier Delattre, Xavier Sastre-Garau, Bernard Asselain, Brigitte Sigal-Zafrani, Jérôme Couturier, Dominique Stoppa-Lyonnet, Henri Magdelénat, Pierre Pouillart, Claude Nos, Alain Fourquet, Yoann Désille, Carolyn Spraggon, Alexander Graham, Andrew Cassidy, Paul Elvin, Yann de Rycke, Anne Vincent-Salomon, Isabelle Bernard-Pierrot, Nicolas Stransky, and Fabien Reyal
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Supplementary Figure 2 from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas
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- 2023
17. Supplementary Figure 1 from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas
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François Radvanyi, Jean Paul Thiery, Olivier Delattre, Xavier Sastre-Garau, Bernard Asselain, Brigitte Sigal-Zafrani, Jérôme Couturier, Dominique Stoppa-Lyonnet, Henri Magdelénat, Pierre Pouillart, Claude Nos, Alain Fourquet, Yoann Désille, Carolyn Spraggon, Alexander Graham, Andrew Cassidy, Paul Elvin, Yann de Rycke, Anne Vincent-Salomon, Isabelle Bernard-Pierrot, Nicolas Stransky, and Fabien Reyal
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Supplementary Figure 1 from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas
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- 2023
18. Supplementary Table 2 from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas
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François Radvanyi, Jean Paul Thiery, Olivier Delattre, Xavier Sastre-Garau, Bernard Asselain, Brigitte Sigal-Zafrani, Jérôme Couturier, Dominique Stoppa-Lyonnet, Henri Magdelénat, Pierre Pouillart, Claude Nos, Alain Fourquet, Yoann Désille, Carolyn Spraggon, Alexander Graham, Andrew Cassidy, Paul Elvin, Yann de Rycke, Anne Vincent-Salomon, Isabelle Bernard-Pierrot, Nicolas Stransky, and Fabien Reyal
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637KB Excel file
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- 2023
19. Data from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas
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François Radvanyi, Jean Paul Thiery, Olivier Delattre, Xavier Sastre-Garau, Bernard Asselain, Brigitte Sigal-Zafrani, Jérôme Couturier, Dominique Stoppa-Lyonnet, Henri Magdelénat, Pierre Pouillart, Claude Nos, Alain Fourquet, Yoann Désille, Carolyn Spraggon, Alexander Graham, Andrew Cassidy, Paul Elvin, Yann de Rycke, Anne Vincent-Salomon, Isabelle Bernard-Pierrot, Nicolas Stransky, and Fabien Reyal
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Completion of the working draft of the human genome has made it possible to analyze the expression of genes according to their position on the chromosomes. Here, we used a transcriptome data analysis approach involving for each gene the calculation of the correlation between its expression profile and those of its neighbors. We used the U133 Affymetrix transcriptome data set for a series of 130 invasive ductal breast carcinomas to construct chromosomal maps of gene expression correlation (transcriptome correlation map). This highlighted nonrandom clusters of genes along the genome with correlated expression in tumors. Some of the gene clusters identified by this method probably arose because of genetic alterations, as most of the chromosomes with the highest percentage of correlated genes (1q, 8p, 8q, 16p, 16q, 17q, and 20q) were also the most frequent sites of genomic alterations in breast cancer. Our analysis showed that several known breast tumor amplicons (at 8p11-p12, 11q13, and 17q12) are located within clusters of genes with correlated expression. Using hierarchical clustering on samples and a Treeview representation of whole chromosome arms, we observed a higher-order organization of correlated genes, sometimes involving very large chromosomal domains that could extend to a whole chromosome arm. Transcription correlation maps are a new way of visualizing transcriptome data. They will help to identify new genes involved in tumor progression and new mechanisms of gene regulation in tumors.
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- 2023
20. Supplementary Figure 3 from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas
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François Radvanyi, Jean Paul Thiery, Olivier Delattre, Xavier Sastre-Garau, Bernard Asselain, Brigitte Sigal-Zafrani, Jérôme Couturier, Dominique Stoppa-Lyonnet, Henri Magdelénat, Pierre Pouillart, Claude Nos, Alain Fourquet, Yoann Désille, Carolyn Spraggon, Alexander Graham, Andrew Cassidy, Paul Elvin, Yann de Rycke, Anne Vincent-Salomon, Isabelle Bernard-Pierrot, Nicolas Stransky, and Fabien Reyal
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Supplementary Figure 3 from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas
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- 2023
21. Androgen Receptor Inhibitor Enhances the Antitumor Effect of PARP Inhibitor in Breast Cancer Cells by Modulating DNA Damage Response
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Paul Elvin, Hyemin Jang, Yaewon Yang, Mark J. O'Connor, Koung Jin Suh, Seock Ah Im, Ahrum Min, Kyung Hun Lee, Debora Keunyoung Kim, and Seongyeong Kim
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0301 basic medicine ,Cancer Research ,DNA Repair ,DNA damage ,Ubiquitin-Protein Ligases ,Down-Regulation ,Mice, Nude ,Breast Neoplasms ,Ataxia Telangiectasia Mutated Proteins ,Poly(ADP-ribose) Polymerase Inhibitors ,Models, Biological ,Piperazines ,Olaparib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Downregulation and upregulation ,Cell Line, Tumor ,Androgen Receptor Antagonists ,medicine ,Animals ,Humans ,Receptor ,Estrogen Receptor Status ,Cell Proliferation ,Homeodomain Proteins ,Mice, Inbred BALB C ,Nuclear Proteins ,medicine.disease ,Xenograft Model Antitumor Assays ,Neoplasm Proteins ,Pyridazines ,Androgen receptor ,030104 developmental biology ,Oncology ,chemistry ,Receptors, Androgen ,030220 oncology & carcinogenesis ,PARP inhibitor ,Cancer research ,Phthalazines ,Female ,DNA Damage ,Transcription Factors - Abstract
The androgen receptor (AR) is expressed in 60%–70% of breast cancers regardless of estrogen receptor status, and has been proposed as a therapeutic target in breast cancers that retain AR. In this study, the authors aimed to investigate a new treatment strategy using a novel AR inhibitor AZD3514 in breast cancer. AZD3514 alone had a minimal antiproliferative effect on most breast cancer cell lines irrespective of AR expression level, but it downregulated the expressions of DNA damage response (DDR) molecules, including ATM and chk2, which resulted in the accumulation of damaged DNA in some breast cancer cells. Furthermore, AZD3514 enhanced cellular sensitivity to a PARP inhibitor olaparib by blocking the DDR pathway in breast cancer cells. Furthermore, the downregulation of NKX3.1 expression in MDA-MB-468 cells by AZD3514 occurred in parallel with the suppression of ATM–chk2 axis activation, and the suppression of NKX3.1 by AZD3514 was found to result from AZD3514-induced TOPORS upregulation and a resultant increase in NKX3.1 degradation. The study shows posttranslational regulation of NKX3.1 via TOPORS upregulation by AZD3514-induced ATM inactivation–increased olaparib sensitivity in AR-positive and TOPORS-expressing breast cancer cells, and suggests the antitumor effect of AZD3514/olaparib cotreatment is caused by compromised DDR activity in breast cancer cell lines and in a xenograft model. These results provide a rationale for future clinical trials of olaparib/AR inhibitor combination treatment in breast cancer.
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- 2018
22. A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in
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Udai, Banerji, Emma J, Dean, J Alejandro, Pérez-Fidalgo, Gerald, Batist, Philippe L, Bedard, Benoit, You, Shannon N, Westin, Peter, Kabos, Michelle D, Garrett, Mathew, Tall, Helen, Ambrose, J Carl, Barrett, T Hedley, Carr, S Y Amy, Cheung, Claire, Corcoran, Marie, Cullberg, Barry R, Davies, Elza C, de Bruin, Paul, Elvin, Andrew, Foxley, Peter, Lawrence, Justin P O, Lindemann, Rhiannon, Maudsley, Martin, Pass, Vicky, Rowlands, Paul, Rugman, Gaia, Schiavon, James, Yates, and Jan H M, Schellens
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Adult ,Male ,Class I Phosphatidylinositol 3-Kinases ,Genital Neoplasms, Female ,Breast Neoplasms ,Middle Aged ,Pyrimidines ,Treatment Outcome ,Area Under Curve ,Mutation ,Biomarkers, Tumor ,Humans ,Female ,Pyrroles ,Molecular Targeted Therapy ,Neoplasm Metastasis ,Protein Kinase Inhibitors ,Proto-Oncogene Proteins c-akt ,Aged ,Neoplasm Staging - Published
- 2017
23. Abstract 3826: CCS1477, a potent and selective p300/CBP bromodomain inhibitor, is targeted & differentiated from BET inhibitors in prostate cancer cell lines in vitro
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Paul Elvin, Amy Prosser, Nigel Brooks, Luke Gaughan, Neil Anthony Pegg, and Barbara Young
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0301 basic medicine ,Cancer Research ,Chemistry ,Cancer ,medicine.disease ,Molecular biology ,TMPRSS2 ,Bromodomain ,BET inhibitor ,Androgen receptor ,03 medical and health sciences ,Prostate cancer ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Gene expression ,medicine - Abstract
Background: CCS1477 is a potent and selective p300/CBP bromodomain inhibitor, currently in a Ph1 trial for patients with metastatic castration resistant prostate cancer (mCRPC). CCS1477 works by inhibiting the expression and function of the androgen receptor (AR), as well as inhibiting c-Myc. Bromodomain and extraterminal domain (BET) protein inhibitors are also being developed in mCRPC. We have established a BET inhibitor (BETi) resistant 22Rv1 prostate cancer cell line and used this, alongside parental 22Rv1 cells, to characterise the differential effects of p300/CBP vs BET bromodomain inhibition. Methods: 22Rv1 cells which express both the wild-type and splice variant forms of AR were cultured in the presence of increasing concentrations (30-500nM) of JQ1 for several months. A parallel set of 22Rv1 cells were cultured in the presence of vehicle (0.1% DMSO). The anti-proliferative effects of JQ1, iBet762, OTX-015 and CCS1477 (10 nm-10 µM dose range) was determined in resistant and parental 22Rv1 cells in a 5d CellTitre Glo assay. The effects of combining CCS1477 with JQ1 was measured in parental 22Rv1 cells. Protein biomarker (AR, AR-splice variant, c-Myc) responses were measured by Western blot and qPCR was used to determine changes in the expression of selected genes (AR, AR-V7, c-Myc, KLK3, TMPRSS2). Gene expression microarrays (Clariom D) were used to assess global gene expression changes in cells treated for 24h with 500nM CCS1477 or JQ1. Results: JQ1 resistant 22Rv1 cells were significantly less sensitive to JQ1 compared with parental cells. (IC50; Res, 7.3 µM vs parental, 0.06 µM). There was also cross-resistance to other chemically distinct BET inhibitors, iBET762 and OTX-015. JQ1 potently inhibited c-Myc protein and gene expression in parental cells, a response that was abrogated in the JQ1 resistant line. The inhibitory effects of JQ1 on AR gene and protein expression were reduced in the resistant line. In contrast potent anti-proliferative effects of CCS1477 were retained in JQ1 resistant cells, as was the inhibitory effect on c-Myc and AR. Combination of CCS1477 & JQ1 resulted in a highly synergistic inhibitory effect on proliferation in normal 22Rv1 cells. Global gene expression analysis revealed significantly fewer altered genes after CCS1477 (27 up, 119 down) compared to JQ1 (196 up, 655 down). Conclusions: These studies provide three lines of evidence for a differentiated mode of action of CCS1477 vs BETi. First, CCS1477 continues to inhibit proliferation and relevant response biomarkers in a cell line that is resistant to BETi. Second, there is a synergistic, rather than additive effect of combining CCS1477 with JQ1. Third, there are significantly fewer genes and a distinct pattern of gene change after CCS1477 vs. JQ1. Collectively, these data point to a differentiated and more selective profile after p300/CBP inhibition with CCS1477. Citation Format: Nigel Brooks, Amy Prosser, Barbara Young, Luke Gaughan, Paul Elvin, Neil Pegg. CCS1477, a potent and selective p300/CBP bromodomain inhibitor, is targeted & differentiated from BET inhibitors in prostate cancer cell lines in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3826.
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- 2019
24. Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer
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Hyun-Jin Nam, Seock-Ah Im, Young-Kwang Yoon, Tae-You Kim, Sae-Won Han, Hwang-Phill Kim, Paul Elvin, Yung-Jue Bang, Ahrum Min, Do-Youn Oh, and Sang-Hyun Song
- Subjects
Cancer Research ,Receptor, ErbB-2 ,Gene Expression ,Mice, Nude ,Pharmacology ,Biology ,medicine.disease_cause ,Lapatinib ,CSK Tyrosine-Protein Kinase ,Mice ,Cell Movement ,Stomach Neoplasms ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Benzodioxoles ,Proto-Oncogene Proteins c-abl ,Cell Proliferation ,Cisplatin ,Mice, Inbred BALB C ,Bcl-2-Like Protein 11 ,Cell growth ,Kinase ,Membrane Proteins ,Cancer ,medicine.disease ,G1 Phase Cell Cycle Checkpoints ,Xenograft Model Antitumor Assays ,Tumor Burden ,src-Family Kinases ,Oncology ,Drug Resistance, Neoplasm ,Quinazolines ,Female ,Fluorouracil ,Apoptosis Regulatory Proteins ,Carcinogenesis ,Tyrosine kinase ,Signal Transduction ,Proto-oncogene tyrosine-protein kinase Src ,medicine.drug - Abstract
Src is a nonreceptor tyrosine kinase involved in the cross-talk and mediation of many signaling pathways that promote cell proliferation, adhesion, invasion, migration, and tumorigenesis. Increased Src activity has been reported in many types of human cancer, including gastric cancer. Therefore, this factor has been identified as a promising therapeutic target for cancer treatments, and targeting Src in gastric cancer is predicted to have potent effects. We evaluated the antitumor effect of a c-Src/Abl kinase inhibitor, saracatinib (AZD0530), alone or combined with chemotherapeutic agents in gastric cancer cell lines and a NCI-N87 xenograft model. Among 10 gastric cancer cell lines, saracatinib specifically inhibited the growth and migration/invasion of SNU216 and NCI-N87 cells. Saracatinib blocked the Src/FAK, HER family, and oncogenic signaling pathways, and it induced G1 arrest and apoptosis in SNU216 and NCI-N87 cells. Apoptosis required induction of the proapoptotic BCL2 family member Bim. Knockdown of Bim using siRNA decreased apoptosis induced by treatment with saracatinib, suggesting that Bim has an important role in saracatinib-induced apoptosis. Saracatinib enhanced the effects of lapatinib, an EGFR/HER2 dual inhibitor, in SNU216 and NCI-N87 cells. Furthermore, combined treatment with saracatinib and 5-fluorouracil (5-FU) or cisplatin exerted synergistic effects in both saracatinib-sensitive and saracatinib-resistant cells. Consistent with our in vitro findings, cotreatment with saracatinib and 5-FU resulted in enhanced antitumor activity in the NCI-N87 xenografts. These data indicate that the inhibition of Src kinase activity by saracatinib alone or in combination with other agents can be a strategy to target gastric cancer. Mol Cancer Ther; 12(1); 16–26. ©2013 AACR.
- Published
- 2013
25. Gene Array and Fluorescence In situ Hybridization Biomarkers of Activity of Saracatinib (AZD0530), a Src Inhibitor, in a Preclinical Model of Colorectal Cancer
- Author
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John J. Arcaroli, S. Gail Eckhardt, Rebecca W. Powell, Paul Elvin, Dexiang Gao, Wells A. Messersmith, Basel M. Touban, Marileila Varella-Garcia, and Aik Choon Tan
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Colorectal cancer ,Immunoblotting ,Antineoplastic Agents ,Apoptosis ,Cell Separation ,Biology ,Article ,Mice ,In vivo ,Cell Line, Tumor ,Gene expression ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Benzodioxoles ,Protein Kinase Inhibitors ,In Situ Hybridization, Fluorescence ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,medicine.diagnostic_test ,Cell growth ,Cancer ,Flow Cytometry ,medicine.disease ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Oncology ,Drug Resistance, Neoplasm ,Quinazolines ,Cancer research ,Colorectal Neoplasms ,Proto-oncogene tyrosine-protein kinase Src ,Fluorescence in situ hybridization - Abstract
Purpose: To evaluate the efficacy of saracatinib (AZD0530), an oral Src inhibitor, in colorectal cancer (CRC) and to identify biomarkers that predict antitumor activity. Experimental Design: Twenty-three CRC cell lines were exposed to saracatinib, and baseline gene expression profiles of three sensitive and eight resistant cell lines in vitro and in vivo were used to predict saracatinib sensitivity in an independent group of 10 human CRC explant tumors using the gene array K-Top Scoring Pairs (K-TSP) method. In addition, fluorescence in situ hybridization (FISH) and immunoblotting determined both Src gene copy number and activation of Src, respectively. Results: Two of 10 explant tumors were determined to be sensitive to saracatinib. The K-TSP classifier (TOX>GLIS2, TSPAN7>BCAS4, and PARD6G>NXN) achieved 70% (7 of 10) accuracy on the test set. Evaluation of Src gene copy number by FISH showed a trend toward significance (P = 0.066) with respect to an increase in Src gene copy and resistance to saracatinib. Tumors sensitive to saracatinib showed an increase in the activation of Src and FAK when compared with resistant tumors. Conclusions: Saracatinib significantly decreased tumor growth in a subset of CRC cell lines and explants. A K-TSP classifier (TOX>GLIS2, TSPAN7>BCAS4, and PARD6G>NXN) was predictive for sensitivity to saracatinib. In addition, increased activation of the Src pathway was associated with sensitivity to saracatinib. These results suggest that FISH, a K-TSP classifier, and activation of the Src pathway have potential in identifying CRC patients that would potentially benefit from treatment with saracatinib. Clin Cancer Res; 16(16); OF1–12. ©2010 AACR. Clin Cancer Res; 16(16); 4165–77. ©2010 AACR.
- Published
- 2010
26. Phase I Safety, Pharmacokinetics, and Inhibition of Src Activity Study of Saracatinib in Patients with Solid Tumors
- Author
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Renee Iacona, Alan Swaisland, José Baselga, Paul Elvin, Andrés Cervantes, Herbert Hurwitz, Esther Casado, Klaas Hoekman, Duncan I. Jodrell, Erika Martinelli, Josep Tabernero, Paul Hamberg, Isabel Chirivella, Baselga, J, Cervantes, A, Martinelli, Erika, Chirivella, I, Hoekman, K, Hurwitz, Hi, Jodrell, Di, Hamberg, P, Casado, E, Elvin, P, Swaisland, A, Iacona, R, Tabernero, J., Medical oncology, and CCA - Innovative therapy
- Subjects
Adult ,Male ,Cancer Research ,Drug-Related Side Effects and Adverse Reactions ,Maximum Tolerated Dose ,Administration, Oral ,Phases of clinical research ,Antineoplastic Agents ,Neutropenia ,Pharmacology ,Drug Administration Schedule ,Young Adult ,Pharmacokinetics ,Neoplasms ,medicine ,Humans ,Benzodioxoles ,Dosing ,Protein Kinase Inhibitors ,Aged ,Dose-Response Relationship, Drug ,business.industry ,Area under the curve ,Middle Aged ,medicine.disease ,Enzyme Activation ,Treatment Outcome ,src-Family Kinases ,Oncology ,Tolerability ,Disease Progression ,Quinazolines ,Female ,Biological half-life ,business ,Febrile neutropenia - Abstract
Purpose: This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of the oral Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors. Experimental Design: Part A of the study followed a multiple-ascending dose design to establish the maximum tolerated dose (MTD) of saracatinib. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing. Results: In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and Cmax of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ∼40 hours. Conclusions: Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d. Clin Cancer Res; 16(19); 4876–83. ©2010 AACR.
- Published
- 2010
27. Regional copy number–independent deregulation of transcription in cancer
- Author
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Jean Paul Thiery, François Radvanyi, Dominique K. Chopin, Isabelle Bernard-Pierrot, Jennifer Southgate, Céline Vallot, Yves Allory, Andrew Cassidy, Sixtina Gil Diez de Medina, Carolyn Spraggon, Paul Elvin, Alexander Graham, Claude C. Abbou, Yann De Rycke, Fabien Reyal, Donna G. Albertson, Bernard Asselain, Rick Segraves, Daniel Pinkel, and Nicolas Stransky
- Subjects
Genetics ,Regulation of gene expression ,Transcription, Genetic ,Gene Dosage ,DNA, Neoplasm ,DNA Methylation ,Biology ,Gene dosage ,Epigenesis, Genetic ,Gene Expression Regulation, Neoplastic ,Transcriptome ,Urinary Bladder Neoplasms ,Cell Line, Tumor ,DNA methylation ,Gene expression ,Histone methylation ,Humans ,Chromosomes, Human, Pair 3 ,Epigenetics ,Gene ,Oligonucleotide Array Sequence Analysis - Abstract
Genetic and epigenetic alterations have been identified that lead to transcriptional deregulation in cancers. Genetic mechanisms may affect single genes or regions containing several neighboring genes, as has been shown for DNA copy number changes. It was recently reported that epigenetic suppression of gene expression can also extend to a whole region; this is known as long-range epigenetic silencing. Various techniques are available for identifying regional genetic alterations, but no large-scale analysis has yet been carried out to obtain an overview of regional epigenetic alterations. We carried out an exhaustive search for regions susceptible to such mechanisms using a combination of transcriptome correlation map analysis and array CGH data for a series of bladder carcinomas. We validated one candidate region experimentally, demonstrating histone methylation leading to the loss of expression of neighboring genes without DNA methylation.
- Published
- 2006
28. Inhibition of human bladder tumour cell growth by fibroblast growth factor receptor 2b is independent of its kinase activity. Involvement of the carboxy-terminal region of the receptor
- Author
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Philippe Broët, Aurélie Caillault, Paul Elvin, Isabelle Bernard-Pierrot, Séverine Lair, Jean Paul Thiery, Alexander Graham, François Radvanyi, David Ricol, and Andrew Cassidy
- Subjects
Cancer Research ,Base Sequence ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Fibroblast growth factor receptor 2 ,Fibroblast growth factor receptor 1 ,Enzyme-Linked Immunosorbent Assay ,Fibroblast growth factor receptor 4 ,Fibroblast growth factor receptor 3 ,Receptors, Fibroblast Growth Factor ,Tropomyosin receptor kinase C ,Receptor tyrosine kinase ,Urinary Bladder Neoplasms ,Growth factor receptor ,Insulin-Like Growth Factor II ,Cell Line, Tumor ,Genetics ,biology.protein ,Cancer research ,Humans ,Receptor, Fibroblast Growth Factor, Type 2 ,Molecular Biology ,Cell Division ,Platelet-derived growth factor receptor ,DNA Primers - Abstract
The b isoform of fibroblast growth factor receptor 2, FGFR2b/FGFR2-IIIb/Ksam-IIC1/KGFR, a tyrosine kinase receptor, is expressed in a wide variety of epithelia and is downregulated in several human carcinomas including prostate, salivary and urothelial cell carcinomas. FGFR2b has been shown to inhibit growth in tumour cell lines derived from these carcinomas. Here, we investigated the molecular mechanisms underlying the inhibition of human urothelial carcinoma cell growth following FGFR2b expression. Using a nylon DNA array, we analysed the gene expression profile of the T24 bladder tumour cell line, transfected or not with a construct encoding FGFR2b. The expression of FGFR2b in T24 cells decreased insulin-like growth factor (IGF)-II mRNA levels. This decrease was correlated with a decrease in IGF-II secretion and may have been responsible for the observed inhibition of cell growth because the addition of exogenous IGF-II restored growth rates to normal levels. Using SU5402, an inhibitor of FGFR tyrosine kinase activity, and a kinase dead mutant of the receptor, FGFR2b Y659F/Y660F, we also demonstrated that the growth inhibition and decrease in IGF-II secretion induced by FGFR2b did not require tyrosine kinase activity. Finally, we demonstrated the involvement of the distal carboxy-terminal domain of the receptor in decreasing IGF-II expression and inhibiting T24 cell growth, as Ksam-IIC3, a variant of FGFR2b carrying a short carboxy-terminus, neither downregulated IGF-II nor inhibited cell proliferation. Our data suggest that FGFR2b inhibits the growth of bladder carcinoma cells by reducing IGF-II levels via its carboxy-terminal domain, independent of its tyrosine kinase activity.
- Published
- 2004
29. Nonclinical selection criteria for maximizing yield of nucleic acid amplification tests in tuberculosis diagnosis
- Author
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Paul Elvin, John Bernardo, and Linda L. Han
- Subjects
Microbiology (medical) ,Adult ,Male ,medicine.medical_specialty ,Tuberculosis ,Disease ,Sensitivity and Specificity ,Mycobacterium tuberculosis ,Tuberculosis diagnosis ,Internal medicine ,mental disorders ,medicine ,Nucleic Acid Amplification Tests ,Humans ,Test selection ,Selection (genetic algorithm) ,Bacteriological Techniques ,biology ,business.industry ,Patient Selection ,Mycobacteriology and Aerobic Actinomycetes ,Nucleic acid amplification technique ,biology.organism_classification ,medicine.disease ,Surgery ,nervous system diseases ,nervous system ,Massachusetts ,Female ,business ,Nucleic Acid Amplification Techniques - Abstract
In spite of the excellent performance of rapid tuberculosis (TB) nucleic acid amplification (NAA) tests and the clear benefits of immediate diagnosis of TB disease, NAA tests frequently are not used in the diagnosis of pulmonary TB cases, particularly TB cases with smear-negative sputa. Public health laboratories primarily perform TB NAA tests only on a targeted subset of specimens, usually including those that are smear positive and those for which a clinician has specifically requested NAA testing. As an alternative to targeted testing, some laboratories use TB NAA tests universally for all respiratory specimens, though this practice can be prohibitively costly and can be associated with an increased frequency of false-positive results due to testing of lower-risk patients. We propose a strategy for identifying individuals for NAA testing on the basis of nonclinical risk criteria that are routinely provided on the test requisition form, such as type of health care facility from which the specimen is received and patient age group. Use of this strategy at the Massachusetts Department of Public Health Laboratory would allow for NAA test identification of approximately 54 (74%) of 72 culture-positive pulmonary TB cases over a 1-year period while requiring NAA testing for only 933 (17%) of 5,469 individuals submitting respiratory specimens. We demonstrate that use of nonclinical NAA test selection criteria is an effective strategy for maximizing the number of TB cases that can be rapidly identified while minimizing the number of specimens that must be tested.
- Published
- 2012
30. False-negative MRI biomarkers of tumour response to targeted cancer therapeutics
- Author
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Jessica K.R. Boult, Paul Elvin, Anderson J. Ryan, John C. Waterton, Yann Jamin, Jane Halliday, L D Gilmour, Simon Walker-Samuel, V Jacobs, and Simon P. Robinson
- Subjects
Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Imaging biomarker ,Colorectal cancer ,Proto-Oncogene Proteins pp60(c-src) ,Vandetanib ,Prostate cancer ,Mice ,Piperidines ,Prostate ,Internal medicine ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Benzodioxoles ,Molecular Targeted Therapy ,False Negative Reactions ,medicine.diagnostic_test ,business.industry ,Cancer ,Mammary Neoplasms, Experimental ,Prostatic Neoplasms ,biomarkers ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,Vascular Endothelial Growth Factor Receptor-2 ,VEGF ,Cell Hypoxia ,Rats ,medicine.anatomical_structure ,Quinazolines ,Blood Vessels ,Female ,Liver cancer ,business ,Translational Therapeutics ,Neoplasm Transplantation ,medicine.drug ,MRI ,Src - Abstract
BACKGROUND: Non-invasive quantitative imaging biomarkers are essential for the evaluation of novel targeted therapeutics. Before deployment in clinical trials, such imaging biomarkers require qualification, typically through pre-clinical identification of imaging-pathology correlates. METHODS: First, in investigating imaging biomarkers of invasion, the response of orthotopic murine PC3 prostate xenografts to the Src inhibitor saracatinib was assessed using susceptibility contrast MRI. Second, the longitudinal response of chemically induced rat mammary adenocarcinomas to the VEGFR2 inhibitor vandetanib was monitored by intrinsic susceptibility MRI, to identify the time window of transient vascular normalisation. RESULTS: No significant differences in fractional blood volume (%), vessel calibre (μm), native T(1) (ms) or apparent water diffusion coefficient were determined, despite reduced expression of activated Fak and paxillin in the saracatinib cohort. Treatment with vandetanib elicited a 60% antitumour response (P
- Published
- 2012
31. Discovery and Development of Drugs Targeting Tumor Invasion and Metastasis
- Author
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Tim P. Green, Paul Elvin, and Robert J. Jones
- Subjects
medicine.hormone ,C-Met ,Bladder cancer ,medicine.medical_treatment ,CD44 ,Biology ,medicine.disease ,Targeted therapy ,Metastasis ,Endothelins ,chemistry.chemical_compound ,Prostate cancer ,Circulating tumor cell ,chemistry ,medicine ,biology.protein ,Cancer research - Published
- 2011
32. Inhibition of Src impairs the growth of met-addicted gastric tumors
- Author
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Stefania Gastaldi, Francesco Galimi, Andrea Bertotti, Livio Trusolino, Cecilia Bracco, Flavia Girolami, Enzo Medico, Davide Torti, Paul Elvin, and Paolo M. Comoglio
- Subjects
Cancer Research ,Proliferation index ,Angiogenesis ,Blotting, Western ,Fluorescent Antibody Technique ,Gene Expression ,Antineoplastic Agents ,Biology ,medicine.disease_cause ,Mice ,Stomach Neoplasms ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Protein Kinase Inhibitors ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,Cell growth ,Gene Expression Profiling ,Cell cycle ,Proto-Oncogene Proteins c-met ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Dasatinib ,src-Family Kinases ,Oncology ,Cancer research ,Carcinogenesis ,Tyrosine kinase ,Proto-oncogene tyrosine-protein kinase Src ,medicine.drug ,Signal Transduction - Abstract
Purpose: We examined whether inhibition of Src tyrosine kinase, a downstream effector of the MET oncogene, can hinder the malignant properties of gastric tumors dependent on Met for growth and survival. Experimental Design: Sensitivity to Src inhibition was determined in vitro by measuring clonogenic survival (anchorage-independent growth) and in vivo by establishing xenograft models. Four “Met-addicted” gastric carcinoma cell lines (GTL16, MKN45, HS746T, and SNU5) and three Met-independent gastric carcinoma cell lines (KATO III, AGS, and NCI-N87) were treated with the Src inhibitor saracatinib (AZD0530). In GTL16 and KATO III, Src neutralization was also achieved by dasatinib and RNA interference. The biochemical and transcriptional consequences of Src inhibition were explored using anti-phosphoprotein antibodies and oligonucleotide microarrays. Results: Inhibition of Src in Met-addicted gastric carcinoma cell lines (a) decreased the phosphorylation/activation levels of signaling intermediates involved in cell proliferation and protection from apoptosis and down-modulated the expression of several cell cycle regulators; (b) reduced anchorage-independent growth; (c) enhanced impairment of cell viability produced by Met inhibition; and (d) delayed tumorigenesis in xenotransplantation models. Immunohistochemical analysis of tumor xenograft tissues following systemic treatment with saracatinib showed a reduction of tumor cell proliferation index, increased apoptosis, and diminished phospho-focal adhesion kinase and phospho-paxillin staining. Tumor stroma parameters such as angiogenesis or inflammatory infiltration were unaffected. In clonogenic survival assays, gastric carcinoma cells without addiction to Met were less sensitive than Met-addicted cells to Src inhibition. Conclusions: Src is as a key downstream transducer of Met-driven tumor growth. Targeting Src might provide therapeutic benefit in Met-addicted tumors. Clin Cancer Res; 16(15); 3933–43. ©2010 AACR.
- Published
- 2010
33. Saracatinib Impairs Head and Neck Squamous Cell Carcinoma Invasion by Disrupting Invadopodia Function
- Author
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Barbara Frederick, Tim P. Green, David Raben, Paul Elvin, Scott A. Weed, Brian L. Rothschild, Lesly Ann Lopez-Skinner, Jason V. Evans, Karen H. Martin, Laura C. Kelley, Karen E. Hayes, and Amanda Gatesman Ammer
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,biology ,business.industry ,Cell ,Perineural invasion ,Matrix metalloproteinase ,medicine.disease ,Head and neck squamous-cell carcinoma ,Article ,Focal adhesion ,stomatognathic diseases ,medicine.anatomical_structure ,Oncology ,Invadopodia ,Cancer research ,medicine ,biology.protein ,business ,Cortactin ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Elevated Src kinase activity is linked to the progression of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Src regulates HNSCC proliferation and tumor invasion, with the Src-targeted small molecule inhibitor saracatinib displaying potent anti-invasive effects in preclinical studies. However, the pro-invasive cellular mechanism(s) perturbed by saracatinib are unclear. The anti-proliferative and anti-invasive effects of saracatinib on HNSCC cell lines were therefore investigated in pre-clinical cell and mouse model systems. Saracatinib treatment inhibited growth, cell cycle progression and transwell Matrigel invasion in HNSCC cell lines. Dose-dependent decreases in Src activation and phosphorylation of the invasion-associated substrates focal adhesion kinase, p130 CAS and cortactin were also observed. While saracatinib did not significantly impact HNSCC tumor growth in a mouse orthotopic model of tongue squamous cell carcinoma, impaired perineural invasion and cervical lymph node metastasis was observed. Accordingly, saracatinib treatment displayed a dose-dependent inhibitory effect on invadopodia formation, extracellular matrix degradation and matrix metalloprotease 9 activation. These results suggest that inhibition of Src kinase by saracatinib impairs the pro-invasive activity of HNSCC by inhibiting Src substrate phosphorylation important for invadopodia formation and associated matrix metalloprotease activity.
- Published
- 2010
34. Walking, cloning, and mapping with yeast artificial chromosomes: A contig encompassing D21S13 and D21S16
- Author
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Paul Elvin, John H. Riley, Alexander F. Markham, R. Butler, R.S. Finniear, Donald J. Ogilvie, G. Slynn, R. Anand, and J. E. N. Morten
- Subjects
Genetic Markers ,Yeast artificial chromosome ,Chromosomes, Human, Pair 21 ,Molecular Sequence Data ,Restriction Mapping ,Molecular cloning ,Biology ,Polymerase Chain Reaction ,Cell Line ,Chromosome Walking ,Restriction map ,Gene mapping ,Genetics ,Primer walking ,Humans ,Cloning, Molecular ,Gene Library ,Repetitive Sequences, Nucleic Acid ,Cloning ,Base Sequence ,Contig ,Genome, Human ,Chromosome Mapping ,DNA ,Electrophoresis, Gel, Pulsed-Field ,Chromosomes, Fungal ,DNA Probes ,Chromosome 21 ,Dinucleoside Phosphates - Abstract
Chromosome 21 has often been used as a model system for the development of genome mapping and cloning strategies in humans. In this report methods for systematic chromosome walking, cloning, and mapping are exemplified in the construction of a 1.5-Mb yeast artificial chromosome (YAC) contig encompassing and extending 400 kb beyond each of the genetic loci D21S13 and D21S16. Isolation of insert-terminal sequences from YACs in this contig provides a set of closely spaced physical markers. These have been used to generate a long-range genomic restriction map.
- Published
- 1992
35. Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530
- Author
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Robin D. Whittaker, Geoffrey A. Holdgate, Vivien Jacobs, M. Fennell, Laurent Francois Andre Hennequin, Judith A. Hargreaves, Brigitte Boyer, Alun Bermingham, Tim P. Green, Jon Curwen, Walter H.J. Ward, Allen Jack Mcqueen, Paul Elvin, Robert W. Wilkinson, Gerard Costello, Patrick Ple, Neil O. Carragher, D. Mark Hickinson, Barry R. Davies, and Armelle Logie
- Subjects
Cancer Research ,Transplantation, Heterologous ,Administration, Oral ,Mice, Nude ,Antineoplastic Agents ,Pharmacology ,Metastasis ,Mice ,Rats, Nude ,Clinical Trials, Phase II as Topic ,In vivo ,Cell Movement ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Benzodioxoles ,Phosphorylation ,Protein Kinase Inhibitors ,Paxillin ,Cell Proliferation ,biology ,Cell migration ,General Medicine ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,Neoplasm Proteins ,Rats ,Transplantation ,src-Family Kinases ,Oncology ,Urinary Bladder Neoplasms ,Tumor progression ,Focal Adhesion Kinase 1 ,Papers ,biology.protein ,NIH 3T3 Cells ,Quinazolines ,Molecular Medicine ,Neoplasm Transplantation ,Proto-oncogene tyrosine-protein kinase Src - Abstract
AZD0530, an orally available Src inhibitor, demonstrated potent antimigratory and anti-invasive effects in vitro, and inhibited metastasis in a murine model of bladder cancer. Antiproliferative activity of AZD0530 in vitro varied between cell lines (IC50 0.2 –> 10 μM). AZD0530 inhibited tumor growth in 4/10 xenograft models tested and dynamically inhibited in vivo phosphorylation of Src substrates paxillin and FAK in both growth-inhibition-resistant and -sensitive xenografts. The activity of AZD0530 in NBT-II bladder cancer cells in vitro was consistent with inhibition of cell migration and stabilization of cell–cell adhesion. These data suggest a dominant anti-invasive pharmacology for AZD0530 that may limit tumor progression in a range of cancers. AZD0530 is currently in Phase II clinical trials.
- Published
- 2009
36. Abstract LB-110: Expression of multiple androgen receptor splice variants in late stage prostate cancer
- Author
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Vivien Jacobs, Margaret Veldman-Jones, Emma Jones, Paul Elvin, Michele Johnstone, Elizabeth A. Harrington, J. Carl Barrett, Zara Ghazoui, and Neil R. Smith
- Subjects
Oncology ,Androgen receptor ,Cancer Research ,medicine.medical_specialty ,Prostate cancer ,Internal medicine ,medicine ,Late stage ,splice ,Biology ,medicine.disease - Abstract
The androgen receptor (AR) remains a key driver of disease progression even with the advent of new therapeutic agents such as abiraterone (A) and enzalutamide (E). Relapse after treatment with A or E has been associated with the emergence of tumour cells expressing AR splice variants, and at least one mutation in AR has been associated with resistance to E. We have investigated the expression of AR splice variants in late stage prostate cancers using Nanostring (nCounter®) to quantify the levels of AR transcripts and by IHC using antibodies targeting the N- and C-terminal AR domains. We also examined the expression of putative AR regulated genes found to be expressed in prostate cancer reported in publically available expression data. Formalin fixed paraffin embedded tissue from 38 commercially sourced (TriStar Technology Group; Asterand; Avaden Biosciences) late stage prostate cancers including 10 castrate resistant prostate cancers (CRPC), were confirmed by pathology review. Total mRNA was isolated from a single 5μm section and gene expression from nCounter® analysis was expressed as normalised Log2 values. Immunohistochemical analysis of AR expression was determined by a pathologist using a H score. Our analysis of AR splice variant expression, relative to a Nanostring detection threshold based on housekeeping genes, has shown the presence of more than one constitutively active AR splice variant in individual tumours. ARV7 was detected in 4/10 CRPC and always found together with ARV1, AR45, and the constitutively active ARV12. All of the CRPC that were negative for ARV7 expressed AR45 and ARV12. Unsupervised clustering of 507 putative AR regulated genes revealed three molecular subgroups among the 38 prostate tumours. One of these subgroups was characterised by the presence of 12/14 AR splice variants including ARV7. Of the other two subgroups, one contained AR45, the other ARV12. Pathway analysis of genes that were expressed to a higher level (>1.5 Log2 fold) in the ARV7 positive compared to ARV7 negative tumours were predominantly associated with cell cycle and proliferation functions. Our data suggests complexity in the molecular landscape of prostate cancer associated with AR splice variants, and that multiple AR splice variants may be of importance to identify patients likely to relapse on treatment with emerging therapy. Citation Format: Zara Ghazoui, Emma Jones, Margaret Veldman-Jones, Vivien N. Jacobs, Neil R. Smith, Michele Johnstone, J. Carl Barrett, Elizabeth A. Harrington, Paul Elvin. Expression of multiple androgen receptor splice variants in late stage prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-110. doi:10.1158/1538-7445.AM2015-LB-110
- Published
- 2015
37. A pharmacokinetically (PK) and pharmacodynamically (PD) driven phase I trial of the pan-AKT inhibitor AZD5363 with expansion cohorts in PIK3CA mutant breast and gynecological cancers
- Author
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Paul Elvin, Andrew Foxley, Shaista Salim, Peter Lawrence, Philippe L. Bedard, Jan H.M. Schellens, Helen Ambrose, Barry R. Davies, Gerald Batist, Udai Banerji, Shannon N. Westin, Emma Dean, Ed Casson, Peter Kabos, Benoit You, Justin P.O. Lindemann, Jose Alejandro Perez-Fidalgo, James W.T. Yates, and Paul Rugman
- Subjects
Oncology ,Target lesion ,Cancer Research ,medicine.medical_specialty ,Akt inhibitor AZD5363 ,business.industry ,Nausea ,Pharmacology ,medicine.disease ,Rash ,Clinical trial ,Breast cancer ,Internal medicine ,Toxicity ,Medicine ,medicine.symptom ,business ,Adverse effect - Abstract
Background: AZD5363 is a novel potent pan-AKT inhibitor (IC50of AKT1, AKT2 and AKT3 of 3, 7 and 7nM respectively) with preclinical activity across a range of models. Methods: The trial had an adaptive design that allowed changes in schedule based on toxicity, PK, and PD findings. AZD5363 was administered orally (PO) twice a day (BID). Three schedules were explored: continuous dosing (7/7), four days a week, (4/7) and two days a week (2/7). PD biomarkers including pAKT, pGSK3?, and pPRAS40 were measured by IHC in pre- and post-treatment tumor biopsies. Once a RP2D was established, two expansion cohorts of PIK3CA-mutant ER+ve breast (B) and gynecological (G) cancers were explored. Results: 47, 21 and 22 patients were treated on the 7/7, 4/7 and 2/7 schedules respectively, with a further 27 and 18 patients recruited to the B and G cohorts to date. The MTDs of 7/7, 4/7 and 2/7 were 320mg BID, 480mg BID and 640mg BID respectively. The dose limiting toxicities (DLTs) were rash and diarrhea for 7/7, and hyperglycemia for 2/7. No DLTs were identified for 4/7. The most common causally-related adverse events CTC Grade 3 were hyperglycemia (20%), diarrhea (10%), rash (10%), nausea (3%) and fatigue (1%). PK profiles at the RP2D of 480mg BID (4/7) showed a multi-dose Css,max of 1426ng/mL and AUCssof 7952ng.hr/mL, which were consistent with exposures that gave tumor regression in preclinical models. Pre- and post-treatment biopsies confirmed target engagement in tumor tissue, with an increase in pAKT and reductions in pGSK3? and pPRAS40. Based on toxicity, PK and PD profiles 480mg BID (4/7) was chosen as the R2PD for single agent AZD5363, with the option of using 640mg BID (2/7) as a pharmacologically active dose for future combination studies. Target lesion shrinkage was observed in 7/15 and 4/14 in the B and G cohorts respectively to date, and with RECIST responses in evaluable patients of 3/15 (20%) and 1/14 (7%). Conclusions: Based on toxicity, PK and PD data two intermittent schedules of AZD5363 have been identified for further exploration. Promising single agent activity has been seen in PIK3CA-mutant breast cancer providing support for ongoing combination studies. Clinical trial information: NCT01226316.
- Published
- 2015
38. Visualizing chromosomes as transcriptome correlation maps: evidence of chromosomal domains containing co-expressed genes--a study of 130 invasive ductal breast carcinomas
- Author
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Bernard Asselain, Claude Nos, Olivier Delattre, Yoann Désille, Dominique Stoppa-Lyonnet, Carolyn Spraggon, Jean Paul Thiery, Pierre Pouillart, Yann De Rycke, François Radvanyi, Brigitte Sigal-Zafrani, Alain Fourquet, Paul Elvin, Alexander Graham, Jérôme Couturier, Henri Magdelenat, Nicolas Stransky, Xavier Sastre-Garau, Isabelle Bernard-Pierrot, Anne Vincent-Salomon, Andrew Cassidy, and Fabien Reyal
- Subjects
Regulation of gene expression ,Genetics ,Cancer Research ,Gene Expression Profiling ,Carcinoma, Ductal, Breast ,Chromosome ,Chromosome Mapping ,Breast Neoplasms ,Biology ,Genome ,Gene expression profiling ,Transcriptome ,Oncology ,Gene mapping ,Chromosomes, Human ,Humans ,Human genome ,RNA, Neoplasm ,Gene ,Oligonucleotide Array Sequence Analysis - Abstract
Completion of the working draft of the human genome has made it possible to analyze the expression of genes according to their position on the chromosomes. Here, we used a transcriptome data analysis approach involving for each gene the calculation of the correlation between its expression profile and those of its neighbors. We used the U133 Affymetrix transcriptome data set for a series of 130 invasive ductal breast carcinomas to construct chromosomal maps of gene expression correlation (transcriptome correlation map). This highlighted nonrandom clusters of genes along the genome with correlated expression in tumors. Some of the gene clusters identified by this method probably arose because of genetic alterations, as most of the chromosomes with the highest percentage of correlated genes (1q, 8p, 8q, 16p, 16q, 17q, and 20q) were also the most frequent sites of genomic alterations in breast cancer. Our analysis showed that several known breast tumor amplicons (at 8p11-p12, 11q13, and 17q12) are located within clusters of genes with correlated expression. Using hierarchical clustering on samples and a Treeview representation of whole chromosome arms, we observed a higher-order organization of correlated genes, sometimes involving very large chromosomal domains that could extend to a whole chromosome arm. Transcription correlation maps are a new way of visualizing transcriptome data. They will help to identify new genes involved in tumor progression and new mechanisms of gene regulation in tumors.
- Published
- 2005
39. Tumour invasion and metastasis: challenges facing drug discovery
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Andrew P. Garner and Paul Elvin
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Pharmacology ,Tumour metastasis ,Pathology ,medicine.medical_specialty ,Drug discovery ,medicine.drug_class ,business.industry ,Ethical standards ,Monoclonal antibody ,medicine.disease ,Tumour invasion ,Metastasis ,Neoplasm Invasiveness ,Drug Design ,Neoplasms ,Drug Discovery ,Matrix metalloproteases ,Cancer research ,medicine ,Humans ,Technology, Pharmaceutical ,Neoplasm Metastasis ,business - Abstract
Initial attempts at directly targeting metastatic spread using inhibitors of matrix metalloproteases failed to deliver the promise of anti-invasive therapy. A new generation of targeted agents with the potential to act as anti-invasives has recently entered the clinic but there is, as yet, no clear route to demonstrate an effect upon tumour metastasis. Because advances with monoclonal antibodies are likely to increase the number of potential anti-invasive agents, more clinically predictive drug discovery cascades are required to reduce the perceived risks associated with their generation. Once they reach the clinic, new approaches will be essential to help early indicators of clinical response meet ethical standards and avoid unnecessary clinical failures.
- Published
- 2005
40. Abstract 738: Increased Ret signalling and impact of vandetanib in acquired tamoxifen resistant breast cancer
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Julia Margaret Wendy Gee, Ian O. Ellis, Carol Mary Dutkowski, Denise Barrow, Rajpal Singh Burmi, Paul Elvin, Lindy Goddard, Iain Robert Hutcheson, Sara L. Pumford, Huw James Mottram, and Robert Ian Nicholson
- Subjects
Cancer Research ,medicine.medical_specialty ,biology ,Kinase ,business.industry ,medicine.drug_class ,Artemin ,Vandetanib ,Tyrosine-kinase inhibitor ,Gefitinib ,Endocrinology ,Oncology ,Internal medicine ,medicine ,Cancer research ,Glial cell line-derived neurotrophic factor ,biology.protein ,business ,Protein kinase B ,Tyrosine kinase ,medicine.drug - Abstract
Deregulation of the tyrosine kinase Ret and its coreceptors (GFRα) has been implicated in neoplasia, and Ret is of interest as a therapeutic target in endocrine-treated breast cancer. This study evaluated in vitro impact of vandetanib, a tyrosine kinase inhibitor able to target Ret in addition to EGFR and VEGFR2, in ER+ breast cancer cells that have acquired resistance to tamoxifen treatment. Tamoxifen resistant TAMR and endocrine responsive MCF7 cells were grown in vitro for 7 days +/- vandetanib (0.5-5μM) +/- exogenous growth factors (10-50ng/ml), and also in continuous culture with vandetanib (1μM), to monitor growth impact and emergence of vandetanib resistance. For Western blotting or immunoprecipitation, log phase cells were transferred for 24hr to serum-free medium and pre-treated for 1hr +/- vandetanib followed by Ret ligands GDNF or artemin for 5mins. Immunohistochemistry for Ret activity was performed on an ER+ tamoxifen-treated clinical breast cancer TMA sample series using Y1062 Ret phospho-antibody with HScore staining assessment. Growth of TAMR cells was substantially inhibited by vandetanib (p These findings demonstrate a central importance for increased Ret signalling and its cross-talk with ER in tamoxifen resistant breast cancer that can be targeted in vitro by vandetanib. Further studies are required to determine optimal combination treatments with vandetanib to circumvent potential intrinsic resistance in clinical breast cancers that exhibit heregulin B1 enrichment. Citation Format: Julia M. Gee, Lindy Goddard, Huw J. Mottram, Rajpal S. Burmi, Sara L. Pumford, Carol M. Dutkowski, Denise Barrow, Iain R. Hutcheson, Robert I. Nicholson, Ian O. Ellis, Paul Elvin. Increased Ret signalling and impact of vandetanib in acquired tamoxifen resistant breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 738. doi:10.1158/1538-7445.AM2014-738
- Published
- 2014
41. Abstract 3957: Analyzing the effects of radiotherapy on the metastatic phenotype: a role for combined therapeutic approaches incorporating Src and PI3K targeting
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Paul Elvin, Emily J. Rowling, Brian A. Telfer, and Kaye J. Williams
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Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Radiation therapy ,Oncology ,In vivo ,medicine ,Cancer research ,business ,Clonogenic assay ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Ex vivo ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Background: Radiotherapy is used in the treatment of over 50% of cancer patients. Although seen as a positive intervention, there are reports of radiation enhancing the metastatic characteristics of cells. We have previously observed that radiotherapy activates a number of pathways associated with tumour metastases and aggressive phenotype including Src and phosphoinositide 3-kinase (PI3K). Here we wished to relate pathway activation to cellular phenotype and to investigate the impact of pharmacological inhibition on radiation response and metastases. Methods: The effects of radiotherapy alone, and combined with Src (AZD0530) and/or PI3K (GDC-0941) inhibition, on cell adhesion, migration and clonogenic survival were assessed in vitro using well-characterised assays. Initial in vivo studies, using FTC133 xenografts, evaluated the effects of radiation treatment on the Src and PI3K pathways and inhibition thereof using pAKT (Ser473) and pFAK (Tyr861) as biomarkers. The effect of single versus combined pathway inhibition with radiation therapy (5x2Gy fractions) on primary tumour growth and lung metastasis (via ex vivo clonogenic assay) was then evaluated. Results: In vitro, radiation combined with Src and/or PI3K inhibition resulted in a reduction in cell adhesion, cell spreading and cell migration compared to radiation alone, with the combined effects greater than either inhibitor alone. Radiation both in vivo and in vitro enhanced activity of the PI3K/AKT and the Src/FAK axis. In vivo, radiation combined with Src or PI3K inhibition showed little effect on tumour growth but did reduce metastatic lung colonisation, compared to radiation alone, with Src inhibition proving more efficacious. When radiation was combined with inhibition of both pathways a significant reduction in both primary tumour growth and metastatic lung colonisation was observed. Conclusion: Radiation enhances multiple pathways, two predominant ones being PI3K and Src, and by using rationale drug combinations we saw improved local control and reduced metastatic spread. From these data we can suggest that the PI3K and Src pathways are involved in the radiation enhancement in metastatic phenotype and this provides potential for application of these therapies in the clinic. Citation Format: Emily J. Rowling, Brian Telfer, Paul Elvin, Kaye J. Williams. Analyzing the effects of radiotherapy on the metastatic phenotype: a role for combined therapeutic approaches incorporating Src and PI3K targeting. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3957. doi:10.1158/1538-7445.AM2014-3957
- Published
- 2014
42. Pharmacodynamic activity of the AKT inhibitor AZD5363 in patients with advanced solid tumors
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J. Carl Barrett, Paul Elvin, Chris Womack, Andrew Foxley, Kenji Tamura, Christine Stephens, Karen E Swales, Matthew Tall, Peter Lawrence, Martin Pass, S.Y. Amy Cheung, Michelle D. Garrett, Amy Palmer, Barry R. Davies, Elizabeth A. Harrington, Helen Ambrose, Udai Banerji, and Justin P.O. Lindemann
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Cancer Research ,Akt inhibitor AZD5363 ,business.industry ,AKT1 ,AKT2 ,medicine.disease ,Small molecule ,AKT3 ,Clinical trial ,Prostate cancer ,Oncology ,Pharmacodynamics ,embryonic structures ,medicine ,Cancer research ,business - Abstract
2541 Background: AZD5363 is an ATP competitive small molecule inhibitor of AKT1, AKT2 and AKT3 and is currently in phase 1 and 2 clinical trials in breast, gynaecological and prostate cancer. In pr...
- Published
- 2014
43. Retrospective evaluation of RET biomarker status and outcome to vandetanib in four phase III randomized NSCLC trials
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Li Zheng, Roy S. Herbst, Jin Soo Lee, James Vasselli, Amanda Gladwin, Richard De Boer, Paul Elvin, Emma Donald, Adam Platt, Chris Womack, John Edward Norris Morten, Xinying Su, and Qunsheng Ji
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Oncology ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Cancer Research ,medicine.medical_specialty ,endocrine system diseases ,business.industry ,Bioinformatics ,Vandetanib ,Internal medicine ,medicine ,Biomarker (medicine) ,RET Fusion ,business ,neoplasms ,medicine.drug - Abstract
8045 Background: The prevalence of the tumorigenic KIF5B:RET fusion gene in NSCLC tumors has been estimated at 0.2–6% (Jiu et al 2012; Lipson et al 2012). We retrospectively analyzed tumor samples from 4 Phase III NSCLC trials of vandetanib, a TKI that selectively targets RET, VEGFR and EGFR signaling, to determine the prevalence of RET fusions and other RET biomarkers, and any potential association with outcome to vandetanib (V). Methods: The studies evaluated were ZODIAC (NCT00312377; docetaxel ± V 100mg), ZEAL (NCT00418886; pemetrexed ± V 100mg), ZEPHYR (NCT00404924; V 300mg vs placebo) and ZEST (NCT00364351; V 300mg vs erlotinib). RET biomarkers evaluated included RET fusions (including KIF5B:RET) and RET gene copy number (assessed by a 4-probe FISH assay), as well as RET protein expression (by IHC). Results: Of 4089 patients randomized across the 4 studies, 1291 and 1234 had tumor samples available for FISH and IHC analysis, respectively, with evaluable data obtained for 944 and 1102. RET fusions (in >10% of tumor cells) were detected in 7 of 944 samples (vandetanib, n=3; comparator, n=4), at a prevalence of 0.7% (95% CI, 0.3–1.5%). None of the 3 vandetanib-treated RET fusion-positive patients had an objective RECIST response, although there was radiologic evidence of tumor shrinkage in 2. Overall, 2.8% (n=26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in >10% tumor cells), 8.1% (n=76) had lower RET gene copy number gain (4–6 copies in ≥40% tumor cells) and 8.3% (n=92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). There was no difference in ORR between vandetanib and comparator for the RET amplification-positive subset (both 8.3% [1/12]), the RET copy number gain subset (9.8% [4/41] vs 9.1% [3/33], respectively) or the RET protein expression-positive subset (15.2% [7/46] and 13.6% [6/44], respectively). Conclusions: The prevalence of RET fusions was estimated at 0.7%. There were too few vandetanib-treated patients with RET fusions to make any firm conclusion regarding association with efficacy. Evidence from the other RET biomarkers tested suggested that these do not infer a differential advantage in patients treated with vandetanib. Clinical trial information: NCT00312377; NCT00418886; NCT00404924.
- Published
- 2013
44. Abstract LB-66: Results of two phase I multicenter trials of AZD5363, an inhibitor of AKT1, 2 and 3: Biomarker and early clinical evaluation in Western and Japanese patients with advanced solid tumors
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Andrea Zivi, Andrew Hastie, Peter Lawrence, Christine Stephens, Paul Elvin, Malcolm R Ranson, Ruud van der Noll, Jan H.M. Schellens, Sy Amy Cheung, Taito Esaki, Kenji Tamura, Marcelo Marotti, Michelle D. Garrett, Paul K. Stockman, Udai Banerji, Barry R. Davies, and Emma Dean
- Subjects
Oncology ,Gerontology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cmax ,Cancer ,medicine.disease ,Pharmacokinetics ,Internal medicine ,Pharmacodynamics ,Toxicity ,medicine ,Dosing ,Adverse effect ,Off Treatment ,business - Abstract
Background: AZD5363 is an oral, potent, and selective inhibitor of AKT1, 2 and 3, with activity in a wide range of tumor cell lines and xenografts dependent upon PI3K/AKT signaling. Methods: Two phase I studies (NCT01226316 [West], NCT01353781 [Japan]) were initiated to define the toxicity, pharmacokinetic (PK), and pharmacodynamic (PD) profile of AZD5363. Two schedules, continuous bid dosing (7/7) and an intermittent schedule bid dosing 4 days on 3 days off (4/7), were investigated. PD biomarkers of AKT signaling were assessed (using pre- and on-treatment samples) in plasma (pPRAS40, pGSK3β, pAKT, glucose, insulin), plucked hair (pPRAS40) and tumor tissue (pPRAS40, pGSK3β, pAKT). Results: At data cut-off (January 2013), 92 patients had been treated in the dose-escalation phases of both studies. In the Western study, the maximum tolerated dose (MTD) for each schedule was 320 mg bid (7/7) and 480 mg bid intermittent dosing (4/7). In the Japanese study, 320 mg bid (7/7) was not tolerated; the MTD for intermittent dosing (4/7) was 480 mg bid. The most commonly reported adverse events, of note, were hyperglycemia, rash, and diarrhea. The PK profile suggests a dose proportional increase in Cmax and AUC. Exposures achieved at doses of 320 mg bid (7/7) and 480 mg bid (4/7) and above are consistent with activity seen in xenograft models. At the doses described, target engagement was seen as evidenced by PD changes in normal tissue (>50% reduction in pPRAS40 in 7/10 patients on AZD5363 480 mg bid (4/7) in plucked hair samples and 30-50% reduction in pPRAS40 and >30% reduction in pGSK3β in platelet rich plasma). Importantly, 7/9 paired biopsies showed an increase in pAKT consistent with the non allosteric inhibition of AKT. Investigation of another intermittent schedule of AZD5363 bid, 2 days on/5 days off treatment, is ongoing. Exploratory mutation analyses of plasma samples are ongoing. Two partial responses were observed, one endometrioid cancer of the ovary and one cervical cancer, in patients on AZD5363 at 480 mg bid (4/7) and 400 mg bid (7/7), respectively. Mutation of either AKT1 or PIK3CA was identified in tumor tissue from both patients. A further patient, with endometrioid cancer of ovary (PIK3CA mutation), had stable disease (SD) for 156 days. Conclusions: AZD5363 administered at 480 mg bid (4/7) was generally well tolerated and showed a PK and PD profile consistent with activity in preclinical models. Partial responses were noted in patients with mutations driving the PI3K pathway. Footnote: AZD5363 was discovered by AstraZeneca subsequent to collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Ltd). Citation Format: Udai Banerji, Malcolm Ranson, Jan HM Schellens, Taito Esaki, Emma Dean, Andrea Zivi, Ruud van der Noll, Paul K. Stockman, Marcelo Marotti, Michelle D. Garrett, Barry R. Davies, Paul Elvin, Andrew Hastie, Peter Lawrence, SY Amy Cheung, Christine Stephens, Kenji Tamura. Results of two phase I multicenter trials of AZD5363, an inhibitor of AKT1, 2 and 3: Biomarker and early clinical evaluation in Western and Japanese patients with advanced solid tumors . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-66. doi:10.1158/1538-7445.AM2013-LB-66
- Published
- 2013
45. Relationship of Src activity and prior oxaliplatin on outcomes after hepatectomy for metastatic colorectal cancer
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Dipen M. Maru, Nila U. Parikh, Paul Elvin, Scott Kopetz, Zhi-Qin Jiang, Van K. Morris, Gary E. Gallick, and Michael J. Overman
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Transition (genetics) ,business.industry ,Colorectal cancer ,medicine.medical_treatment ,medicine.disease ,In vitro ,Oxaliplatin ,Internal medicine ,medicine ,Hepatectomy ,business ,Tyrosine kinase ,Proto-oncogene tyrosine-protein kinase Src ,medicine.drug - Abstract
3561 Background: The nonreceptor tyrosine kinase Src regulates pathways critical to tumor proliferation, chemoresistance, and epithelial-to-mesenchymal transition. In vitro, Src is activated after acute oxaliplatin exposure and in acquired oxaliplatin resistance, but not after 5-FU alone. Activation of Src and its substrate FAK in metastatic colorectal cancer treated with oxaliplatin has not been studied in human specimens. Methods: Samples from 170 hepatic resections from two cohorts of patients with metastatic colorectal cancer were examined by IHC for expression of activated Src (pSrc) and FAK (total and pFAK). In the first cohort (n=50), tissue was collected at consecutive hepatic resections before and after oxaliplatin. Patients in the second cohort (n=120) were compared based on whether or not oxaliplatin was administered after resection. IHC was graded semi-quantitatively, 0 to 4 based on intensity (first cohort), and by automated image analysis (second cohort). Results: In the first cohort, pFAK expression increased after oxaliplatin exposure (mean IHC score 2.04 vs. 1.18, p
- Published
- 2012
46. Abstract 2250: Combination of PARP inhibitor, Olaparib with pathway-targeted drug, vandetanib (Caprelsa™) in TNBC: A proof of principle study to determine the role of PI3K-AKT-mTOR or RAS-MAPK pathways in targeted drug-response
- Author
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Pradip De, Wu Hui, Brian Leyland-Jones, Yuliang Sun, Paul Elvin, and Nandini Dey
- Subjects
MAPK/ERK pathway ,Cancer Research ,biology ,business.industry ,Pharmacology ,Vandetanib ,Olaparib ,chemistry.chemical_compound ,Oncology ,chemistry ,PARP inhibitor ,medicine ,biology.protein ,PTEN ,business ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Triple-negative breast cancer ,medicine.drug - Abstract
Introduction: Identification of the driving genetic alteration(s) (e.g. BRCA, PTEN) and deregulated signaling pathway(s) are critical for the successful discovery of molecular targets in Triple Negative Breast Cancer (TNBC). Understanding of the biology of TN tumor cells has resulted in the recognition of a few molecular targets for the development of novel therapeutics including, (1) cell surface receptor tyrosine kinase(s) (RTKs, e.g. EGFR), (2) signaling pathway(s) (PI3K-mTOR, RAS-MAPK), and (3) DNA-damage (chemo- or radiotherapy) repair pathway. We hypothesize that the genetic background (expression of RTKs, BRCA mutations, absence of PTEN or activating mutations of PIK3CA / RAF) influences the response of TNBC cells to a combination treatment of drugs. Methods: We tested the effects of combination of EGFR/VEGFR inhibitor (vandetanib) with PARPi (Olaparib) in presence of DNA-damaging agent (carboplatin) on, (a) cell survival/proliferation and their, signaling marker(s), (b) integrin-directed migration, (c) fibronectin-directed matrigel-invasion, (d) adhesion-dependent survival, (e) vascular mimicry (VM), and (f) clonogenic survival in TNBC cell lines with high expression of EGFR (MDA-MB468, SUM149), BRCA mutations (HCC1937, SUM149), no expression of PTEN protein (HCC70, HCC1937, MDA-MB468, SUM149), PIK3CA mutation (BT20), and RAS/RAF mutation (MDA-MB231). Results: Data showed that, (1) although EC50s ranged from 5-15 µM for vandetanib in cells, the PTEN-null cells exhibited comparatively favorable EC50s, (2) vandetanib (10 µM) inhibited phosphorylation of AKT (S473 & T308), S6RP, 4EBP1 and ERK by 1 hour, (3) MDA-MB468 cell line was the most sensitive to vandetanib (∼ 0.05 µM) when combined with 10 µM fixed dose of Olaparib, and (4) a combination of vandetanib with Olaparib plus carboplatin time dependently increased caspase-3 and PARP cleavage, inhibited VM (6, 24 h), blocked fibronectin-directed migration, and suppressed clonogenic growth to a greater extent in PTEN-null cells lines. Conclusion: Anti-proliferative/pro-apoptotic, and anti-migratory/invasive effects of vandetanib (alone or in combination with carboplatin plus Olaparib) were most prominent in PTEN-null and high EGFR-expressing cells. However, given that the inhibitory activity of olaparib occurred at relatively high concentrations we are currently pursuing studies to refine the dose response relationship. In addition we are examining (1) the mechanistic relationship between the anti-proliferative/pro-apoptotic effects and the effectors status of EGFR/ PI3K pathway following treatment with vandetanib (in combination with PARPi plus temozolomide), and (2) effect of vandetanib on the hypoxic-response of tumor and endothelial cells, the results of which will be presented in the meeting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2250. doi:1538-7445.AM2012-2250
- Published
- 2012
47. The potential of circulating microRNA (miRNA) levels as a biomarker in drug development: An analysis of tumor-serum samples from patients on a phase I trial of saracatinib-paclitaxel (P)-carboplatin (C)
- Author
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Jacob U. Fog, U. Emeribe, Adam Baker, C. Glue, Christine Stephens, Gilles Freyer, J. Walker, Steinar Aamdal, Paul Elvin, D. S. Tan, Epie Boven, Robert Jones, S. B. Kaye, Eric Pujade-Lauraine, M Stuart, and M. Wrang Teilum
- Subjects
Cancer Research ,Cellular differentiation ,Biology ,Molecular biology ,Carboplatin ,Circulating MicroRNA ,chemistry.chemical_compound ,Oncology ,Drug development ,Paclitaxel ,chemistry ,Apoptosis ,microRNA ,Cancer research ,Biomarker (medicine) ,human activities - Abstract
10548 Background: miRNAs are small non-coding RNAs of 20-25 nucleotides with diverse regulatory functions including proliferation, cell differentiation and apoptosis. Unlike mRNA, miRNAs are stable...
- Published
- 2011
48. Abstract 558: Targeting tumour heparanase activity using fully human monoclonal antibodies
- Author
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Chadwick T. King, Sarah Ross, Ian Foltz, Oscar Pan, Paul Elvin, and Palaniswami Rathanaswami
- Subjects
Cancer Research ,biology ,medicine.drug_class ,Cell ,Heparan sulfate ,Monoclonal antibody ,Molecular biology ,law.invention ,Extracellular matrix ,chemistry.chemical_compound ,medicine.anatomical_structure ,Oncology ,chemistry ,law ,biology.protein ,medicine ,Recombinant DNA ,Heparanase ,Antibody ,Receptor - Abstract
Modification of heparan sulfate proteoglycans (HSPG) in the tumour microenvironment can have a significant influence on tumour cell behavior, tumour growth and metastasis. HSPG play an important role in shaping the integrity of the extracellular matrix, and cell surface HSPG are determinants of cell-cell interactions and receptor function. Heparanase (Hpa1), an endoglycosidase, cleaves the glycosidic bonds within heparan sulfate domains resulting in HSPG with impaired or altered functionality. Elevated expression of heparanase has been correlated with disease progression and poor survival in a number of human cancers. Using Xenomouse™ technology and immunising with recombinant human Hpa1, we have generated fully human monoclonal antibodies that bind to heparanase with high affinity ( Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 558. doi:10.1158/1538-7445.AM2011-558
- Published
- 2011
49. Abstract 1372: Cediranib alone and in combination with mechanistically distinct antitumor therapies in vivo
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Rajesh Odedra, Juliane M. Jürgensmeier, Anderson J. Ryan, Paul D. Smith, Philippa Wood, Stephen R. Wedge, Donald J. Ogilvie, Robert W. Wilkinson, Paula J. Valentine, Armelle Logie, Sharon Barnett, Jane Kendrew, and Paul Elvin
- Subjects
Cancer Research ,business.industry ,Cancer ,Pharmacology ,medicine.disease ,Gemcitabine ,Oxaliplatin ,Cediranib ,Irinotecan ,Pemetrexed ,Oncology ,Docetaxel ,medicine ,Lung cancer ,business ,medicine.drug - Abstract
Cediranib (RECENTIN™) is a highly potent vascular endothelial growth factor (VEGF) signaling inhibitor of all three VEGF receptors that is suitable for once-daily oral dosing. Cediranib is currently in Phase III development in first-line colorectal cancer and recurrent glioblastoma. Work is ongoing to determine its potential utility in a range of other tumors including lung cancer. The aim of these preclinical studies was to examine the effect of combining cediranib with the following mechanistically distinct antitumor therapies: saracatinib (AZD0530; Src inhibitor), AZD6244 (MEK 1/2 inhibitor), 5-fluorouracil (5-FU), docetaxel, cisplatin, oxaliplatin, gemcitabine, pemetrexed and irinotecan. Details of the combination dosing schedules and xenograft models are provided in Table 1. Tumor cells grown in vitro were injected subcutaneously into the dorsal flank of female athymic mice (Swiss nu/nu genotype, ≥6 weeks of age). Mice were randomized into treatment groups (9-15 per group) once the mean tumor volume reached ∼200 mm3. When cediranib was dosed with parenterally administered agents, cediranib administration preceded that of the parenteral therapy by 2 hours. Antitumor effects were assessed by comparing mean tumor size at the end of the dosing period (12-28 days, depending on the model; Table 1) and significance was determined using the t-test (P100100 Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1372.
- Published
- 2010
50. Erratum: Corrigendum: Regional copy number–independent deregulation of transcription in cancer
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François Radvanyi, Dominique Chopin, Fabien Reyal, Bernard Asselain, Isabelle Bernard-Pierrot, Jennifer Southgate, Andrew Cassidy, Céline Vallot, Yann De Rycke, Alexander Graham, Rick Segraves, Daniel Pinkel, Claude C. Abbou, Donna G. Albertson, Carolyn Spraggon, Yves Allory, Paul Elvin, Nicolas Stransky, Sixtina Gil Diez de Medina, and Jean Paul Thiery
- Subjects
Transcription (biology) ,Genetics ,Computational biology ,Biology - Abstract
Nature Genetics 38, 1386–1396 (2006); published online 12 November 2006; corrected after print 27 February 2008 In the version of this article initially published, the horizontal dashed lines representing the threshold value in the panels in row b of Figures 2 and 4 were incorrectly placed. The errors have been corrected in the HTML and PDF versions of this article.
- Published
- 2008
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