DOCSLIB.ORG

Early Clinical Development of Targeted Anticancer Agents

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Early Clinical Development of Targeted Anticancer Agents EARLY CLINICAL DEVELOPMENT OF TARGETED ANTICANCER AGENTS Emilie M.J. van Brummelen Printing of this thesis was fi nancially supported by o Utrecht University o Oncology Graduate School Amsterdam Lay out Emilie M.J. van Brummelen Printed by ProefschriftMaken - www.proefschriftmaken.nl © Emilie M.J. van Brummelen, 2017 The research described in this thesis was conducted at the Department of Pharmacology, the Division of Molecular Pathology of the Netherlands Cancer Institute and the Clinical Research Unit of the Antoni van Leeuwenhoek hospital. EARLY CLINICAL DEVELOPMENT OF TARGETED ANTICANCER AGENTS Klinische ontwikkeling van doelgerichte antikanker therapieën (met een samenvatting in het Nederlands) PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnifi cus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op maandag 18 december 2017 des middags te 2.30 uur door EMILIE MARIE JEANNE VAN BRUMMELEN geboren op 14 april 1989 te Rotterdam Promotoren: Prof. dr. J.H.M. Schellens Prof. dr. J.H. Beijnen TABLE OF CONTENTS Preface Chapter 1 Strategies for development of novel anticancer therapies Chapter 1.1 The performance of model-based versus rule-based phase I clinical trials in 12 oncology. J Pharmacokin Pharmacodyn 2016 Jun; 43(3):235-42 Chapter 1.2 Anti-drug antibody formation in oncology: clinical relevance and challenges. 36 The Oncologist 2016 Oct; 21(10):1260-126 Chapter 2 Combining targeted agents for the treatment of KRAS mutant tumors Chapter 2.1 Phase I study of afatinib plus selumetinib in patients with KRAS-mutation positive colorectal, non-small cell lung and pancreatic cancer. 62 Interim analysis Chapter 2.2 Phase I study of dacomitinib plus PD-0325901 in patients with KRAS-mutation positive colorectal, non-small cell lung and pancreatic cancer. 76 Interim analysis Chapter 2.3 Phase I study of lapatinib plus trametinib in patients with KRAS-mutation 92 positive colorectal, non-small cell lung and pancreatic cancer. Interim analysis Chapter 2.4 Quantifi cation of the exposure-toxicity relationship of combined MEK and pan- HER inhibitors in patients with KRAS mutated tumors. 108 Manuscript in preparation Chapter 3 Phase I studies with biological targeted anticancer agents Chapter 3.1 89Zr-labeled CEA-targeted IL-2 variant immunocytokine in patients with solid tumors: role of IL-2 receptor-binding and CEA-mediated tumor accumulation. 124 Submitted for publication Chapter 3.2 Preliminary effi cacy and safety of pembrolizumab in nine diff erent solid tumor types. 142 Interim analysis Chapter 3.3 Clinical safety and effi cacy of pembrolizumab in patients with malignant pleural mesothelioma: preliminary results from the phase 1b, non-randomized, open- 154 label KEYNOTE-028 trial. The Lancet Oncology 2017 May;18(5): 623-630 Chapter 4 BRAF status as predictive biomarker Chapter 4.1 BRAF mutations as predictive marker for response to anti-EGFR monoclonal 170 antibodies. The Oncologist 2017 Jul; 22(7): 864-872 Chapter 5 Conclusions and perspectives 186 APPENDIX Summary 192 Nederlandse samenvatting List of publications Affi lliations Dankwoord Curriculum vitae PREFACE Cancer is the disease for which most drugs are being developed at the moment1. In 2016, about 40% of the newly approved drugs in Europe were for the treatment of cancer2,3. Initially, most anticancer drugs belonged to the group of cytotoxic anticancer drugs which exert their antican- cer eff ect by interfering with cell replication and survival, mainly in rapidly replicating cells. Over the last years, the focus was shifted to development of the so-called targeted agents. Targeted agents are designed to target specifi c proteins that are overexpressed by or mutated in cancer cells or proteins that induce growth of cancer cells. Promising anticancer eff ects of targeted therapies have been reported. Unfortunately, tolerability of these agents and treatment resistance remain major hurdles. In 2013, a novel strategy garnered attention after the high impact journal ‘Science’ rewarded immunotherapy for cancer as the breakthrough of the year4. Immuno- therapies are designed to activate immune-responses towards cancer cells and hereby enable destruction of cancer cells by the immune system. Although immunotherapies are often defi ned as a separate group, they also belong to the group of targeted anticancer agents. With the use of targeted therapies, the concept of ‘personalized medicine’ became increasingly relevant. Tar- geted therapies enable selection of patients who are most likely to benefi t from treatment. The applied selection criteria are usually defi ned as biomarkers, which are included in all studies described in this thesis. Although this concept of personalized medicine based on biomarkers sounds promising, this approach can only be success- ful when some conditions are met. First, the right biomarkers should be used, to allow adequate selection of patients. Secondly, the drug should reach its target, mostly a specifi c protein in or around the tumor cells, to in- duce an anti-tumor eff ect. The third important factor for every drug is the balance between effi cacy and toxicity. Especially for anticancer drugs, the search for the optimal effi cacy and tolerability can be complicated. Fourthly, effi cacy can be enhanced by combining two or more agents. Combinations can induce a synergistic antitumor eff ect but can also delay or avoid resistance, which often occurs fast in single agent therapies. This thesis focuses on the early stage of clinical development of novel anticancer agents with a focus on phase I trials. Phase I trials often cover the fi rst-in human application of a novel agent or a novel combination, in which the aim is to evaluate the safety of the drug or combination and to determine the optimal dose and regimen. If feasible, phase I trials are followed by phase II, III and IV trials, which focus more on the effi cacy and safety in large populations and compare the novel drug to existing therapies. We describe the results of phase I trials with targeted anticancer agents and present recommendations for the design of future phase I trials, focusing on the challenges that have to be faced now and in the future in early clinical development. Chapter 1 focuses on general aspects of early development of anticancer agents. In Chapter 1.1, the design of phase I clinical trials with targeted anticancer agents is reviewed. We discuss how the design of phase I trials relates to their performance in terms of trial duration and the number of patients needed. Chapter 1.2 focuses on immunotherapies. One of the challenges in the development of immunotherapeutic drugs is their immuno- genicity. After administration, immune responses can occur in which antibodies are formed that are directed towards the drug (anti-drug antibodies). We discuss the incidence, consequences and strategies to deal with anti-drug antibodies in future clinical trials. In chapter 2, the results of combining targeted agents to overcome treatment resistance is described. Chapter 2.1, 2.2 and 2.3 are based on results of three phase I studies with MEK and pan-HER inhibitors. In chapter 2.4, data from these three studies are merged in order to explore the relationship between exposure to MEK and HER inhibitors and toxicity. Based on a pharmacokinetic-toxicodynamic model, recommendations for rational dosing strategies for these combinations are provided. In chapter 3, three phase I trials with immunotherapies are described. Chapter 3.1 provides results on the drug disposition of a novel immunocytokine, consisting of a carcinoembryonic antigen (CEA) antibody and an interleukin-2 variant, in a fi rst-in-human setting. Chapter 3.2 and 3.3 focus on the effi cacy and safety of the anti-programmed death (PD) 1 antibody pembrolizumab in a variety of solid tumors with confi rmed PD-ligand (L) 1 expression. Chapter 4 describes the utility of BRAF status as a biomarker for response to treatment with anti-EGFR mono- clonal antibodies. Several studies indicate that mutations in the BRAF gene induce resistance to treatment with these agents. By upfront screening on genetic alterations in BRAF, we may be able to select patients for whom maximum treatment benefi t is expected. In this chapter, we discuss the impact of these mutations on treatment response. Finally, a refl ection on the combined results of the research described in this thesis is presented in chapter 5. Herein, the future perspectives of previously described anticancer agents and the future challenges in early clini- cal development are discussed. References 1 Pregelj L, Verreynne M-L, Hine D. Changes in clinical trial length. Nat Rev Drug Discov. 2015;14(5):307-308. 2 European Medicines Agency. Annual Report 2016.; 2016. http://www.ema.europa.eu/docs/en_ GB/document_library/Annual_report/2017/05/WC500227334.pdf. Accessed July 12, 2017. 3 Grosios N. EMA anticancer drug approval recommendations in 2015. SMS Oncology. https://sms- oncology.com/blog/ema-anticancer-drug-approval-recommendations-in-2015. Published 2016. Ac cessed January 1, 2017. 4 Couzin-Frankel J. Cancer Immunotherapy. Science (80). 2013;342(6165):1432-1433. “Per aspera ad astra” 9 Chapter 1 Strategies for development of novel an cancer therapies 11 Chapter 1.1 The performance of model-based versus rule-based phase I clinical trials in oncology A quan ta ve comparison of the performance of model-based versus rule-based phase I trials with molecularly targeted an cancer drugs over the last two years Journal of PharmacokineƟ cs and Pharmacodynamics 2016 Jun; 43(3):235-42 Emilie M.J. van Brummelen Alwin D.R. Huitema Erik van Werkhoven Jos H. Beijnen Jan H.M. Schellens ABSTRACT Phase I studies with anticancer drugs are used to evaluate safety and tolerability and to choose a recommended phase II dose (RP2D).
Load more

Recommended publications
  • Resistance Mechanisms to Targeted Therapies in ROS1+ and ALK+ Non−Small Cell Lung Cancer
    Published OnlineFirst April 10, 2018; DOI: 10.1158/1078-0432.CCR-17-2452 Cancer Therapy: Clinical Clinical Cancer Research Resistance Mechanisms to Targeted Therapies in ROS1þ and ALKþ Non–small Cell Lung Cancer Caroline E. McCoach1, Anh T. Le2, Katherine Gowan3, Kenneth Jones3, Laura Schubert2, Andrea Doak2, Adriana Estrada-Bernal2, Kurtis D. Davies4, Daniel T. Merrick4, Paul A. BunnJr2, W. Tom Purcell2, Rafal Dziadziuszko5, Marileila Varella-Garcia2, Dara L. Aisner4, D. Ross Camidge2, and Robert C. Doebele2 Abstract Purpose: Despite initial benefit from tyrosine kinase inhibitors and b-catenin mutations and HER2-mediated bypass signaling as þ (TKIs), patients with advanced non–smallcelllungcancer(NSCLC) non-ROS1–dominant resistance mechanisms. In the ALK þ þ harboring ALK (ALK )andROS1 (ROS1 ) gene fusions ultimately cohort, we identified a novel NRG1 gene fusion, a RET fusion, progress. Here, we report on the potential resistance mechanisms 2 EGFR, and 3 KRAS mutations, as well as mutations in IDH1, þ þ in a series of patients with ALK and ROS1 NSCLC progressing RIT1, NOTCH, and NF1. In addition, we identified CNV in on different types and/or lines of ROS1/ALK–targeted therapy. multiple proto-oncogenes genes including PDGFRA, KIT, KDR, Experimental Design: We used a combination of next-gener- GNAS, K/HRAS, RET, NTRK1, MAP2K1, and others. ation sequencing (NGS), multiplex mutation assay, direct DNA Conclusions: We identified a putative TKI resistance mech- þ sequencing, RT-PCR, and FISH to identify fusion variants/partners anism in six of 12 (50%) ROS1 patients and 37 of 43 (86%) þ and copy-number gain (CNG), kinase domain mutations (KDM), ALK patients.
    [Show full text]
  • S41598-018-33190-8.Pdf
    www.nature.com/scientificreports OPEN Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Received: 20 February 2018 Accepted: 25 September 2018 Osimertinib in EGFR-mutant Lung Published: xx xx xxxx Cancer Akiko Takahashi1, Masahiro Seike1, Mika Chiba1, Satoshi Takahashi1, Shinji Nakamichi1, Masaru Matsumoto1, Susumu Takeuchi1, Yuji Minegishi1, Rintaro Noro1, Shinobu Kunugi2, Kaoru Kubota1 & Akihiko Gemma1 Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is critical in combating EGFR-mutant non-small cell lung cancer (NSCLC). We tried to construct a novel therapeutic strategy to conquer the resistance to second-and third-generation EGFR-TKIs in EGFR-positive NSCLC patients. We established afatinib- and osimertinib-resistant lung adenocarcinoma cell lines. Exome sequencing, cDNA array and miRNA microarray were performed using the established cell lines to discover novel therapeutic targets associated with the resistance to second-and third-generation EGFR-TKIs. We found that ANKRD1 which is associated with the epithelial- mesenchymal transition (EMT) phenomenon and anti-apoptosis, was overexpressed in the second-and third-generation EGFR-TKIs-resistant cells at the mRNA and protein expression levels. When ANKRD1 was silenced in the EGFR-TKIs-resistant cell lines, afatinib and osimertinib could induce apoptosis of the cell lines. Imatinib could inhibit ANKRD1 expression, resulting in restoration of the sensitivity to afatinib and osimertinib of EGFR-TKI-resistant cells. In EGFR-mutant NSCLC patients, ANKRD1 was overexpressed in the tumor after the failure of EGFR-TKI therapy, especially after long-duration EGFR- TKI treatments. ANKRD1 overexpression which was associated with EMT features and anti-apoptosis, was commonly involved in resistance to second-and third-generation EGFR-TKIs.
    [Show full text]
  • Gefitinib and Afatinib Show Potential Efficacy for Fanconi Anemia−Related Head and Neck Cancer
    Published OnlineFirst January 31, 2020; DOI: 10.1158/1078-0432.CCR-19-1625 CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY Gefitinib and Afatinib Show Potential Efficacy for Fanconi Anemia–Related Head and Neck Cancer Helena Montanuy1, Agueda Martínez-Barriocanal2,3, Jose Antonio Casado4,5, Llorenc¸ Rovirosa1, Maria Jose Ramírez1,4,6, Rocío Nieto2, Carlos Carrascoso-Rubio4,5, Pau Riera6,7, Alan Gonzalez 8, Enrique Lerma7, Adriana Lasa4,6, Jordi Carreras-Puigvert9, Thomas Helleday9, Juan A. Bueren4,5, Diego Arango2,3, Jordi Minguillon 1,4,5, and Jordi Surralles 1,4,5 ABSTRACT ◥ Purpose: Fanconi anemia rare disease is characterized by bone two best candidates, gefitinib and afatinib, EGFR inhibitors marrow failure and a high predisposition to solid tumors, especially approved for non–small cell lung cancer (NSCLC), displayed head and neck squamous cell carcinoma (HNSCC). Patients with nontumor/tumor IC50 ratios of approximately 400 and approx- Fanconi anemia with HNSCC are not eligible for conventional imately 100 times, respectively. Neither gefitinib nor afatinib therapies due to high toxicity in healthy cells, predominantly activated the Fanconi anemia signaling pathway or induced hematotoxicity, and the only treatment currently available is sur- chromosomal fragility in Fanconi anemia cell lines. Importantly, gical resection. In this work, we searched and validated two already both drugs inhibited tumor growth in xenograft experiments in approved drugs as new potential therapies for HNSCC in patients immunodeficient mice using two Fanconi anemia patient– with Fanconi anemia. derived HNSCCs. Finally, in vivo toxicity studies in Fanca- Experimental Design: We conducted a high-content screening deficient mice showed that administration of gefitinib or afatinib of 3,802 drugs in a FANCA-deficient tumor cell line to identify was well-tolerated, displayed manageable side effects, no toxicity nongenotoxic drugs with cytotoxic/cytostatic activity.
    [Show full text]
  • Curriculum Vitae
    Professor Barry V L Potter Publications (1979 - 2015) Papers in refereed journals, patents, reviews and book chapters JOURNAL PAPERS 1. The effect of 17O and the magnitude of the 18O isotope shift in 31P nuclear magnetic resonance spectroscopy. G Lowe, B V L Potter, B S Sproat and W E Hull, J Chem Soc Chem Commun (1979) 733- 735. 2. Bacteriostatic properties of fluoro-analogues of 5(2-hydroxyethyl)-4-methyl thiazole, a metabolic intermediate in thiamine biosynthesis. G Lowe and B V L Potter, J Chem Soc Perkin Trans I (1980) 9, 2026-2028. 3. The synthesis, absolute configuration and circular dichroism of the enantiomers of fluorosuccinic acid. G Lowe and B V L Potter, J Chem Soc Perkin Trans I (1980) 9, 2029-2032. 4. Evidence against a step-wise mechanism for the fumarase-catalysed dehydration of (2S)- malate. V T Jones, G Lowe and B V L Potter, Eur J Biochem (1980) 108, 433-437. 5. A stereochemical investigation of the cyclisation of D-glucose-6[16O,17O,18O]-phosphate and adenosine 5'[16O,17O,18O]-phosphate. R L Jarvest, G Lowe and B V L Potter, J Chem Soc Chem Commun (1980) 1142-1145. 6. The stereochemistry of phosphoryl transfer. G Lowe, P M Cullis, R L Jarvest, B V L Potter and B S Sproat, Phil Trans Roy Soc Lond Ser B (1981) 293, 75-92. 7. The stereochemistry of 2-substituted-2-oxo-4,5-diphenyl-1,3,2-dioxaphospholanes and the related chiral [16O,17O,18O]-phosphate monoesters. P M Cullis, R L Jarvest, G Lowe and B V L Potter, J Chem Soc Chem Commun (1981) 245- 246.
    [Show full text]
  • Version Introducing VHIO Foreword
    2017SCIENTIFIC REPORT Vall d'Hebron Institute of Oncology (VHIO) CELLEX CENTER C/Natzaret, 115 – 117 08035 Barcelona, Spain Tel. +34 93 254 34 50 www.vhio.net Direction: Amanda Wren Design: Parra estudio Photography: Katherin Wermke Vall d'Hebron Institute of Oncology (VHIO) | 2018 VHIO Scientific Report 2017 Index Scientific Report INTRODUCING VHIO CORE TECHNOLOGIES 02 Foreword 92 Cancer Genomics Group 08 2017: marking the next chapter of 94 Molecular Oncology Group VHIO's translational story 96 Proteomics Group 18 Scientific Productivity: research articles VHIO'S TRANSVERSAL CLINICAL 19 Selection of some of the most relevant TRIALS CORE SERVICES & UNITS articles by VHIO researchers published in 2017 100 Clinical Trials Office 25 A Golden Decade: reflecting on the 102 Research Unit for Molecular Therapy past 10 years of VHIO's translational of Cancer (UITM) – ”la Caixa” success story 104 Clinical Research Oncology Nurses 106 Clinical Research Oncology Pharmacy PRECLINICAL RESEARCH Unit 49 From the Director 50 Experimental Therapeutics Group RECENTLY INCORPORATED GROUPS 52 Growth Factors Group 110 Cellular Plasticity & Cancer Group 54 Mouse Models of Cancer Therapies 112 Experimental Hematology Group Group 114 Tumor Immunology 56 Tumor Biomarkers Group & Immunotherapy Group 116 Applied Genetics of Metastatic Cancer TRANSLATIONAL RESEARCH Group 61 From the Director 118 Chromatin Dynamics in Cancer Group 62 Gene Expression & Cancer Group 120 Prostate Cancer Translational Research Group 64 Stem Cells & Cancer Group 122 Radiomics Group CLINICAL
    [Show full text]
  • Pushing Estrogen Receptor Around in Breast Cancer
    Page 1 of 55 Accepted Preprint first posted on 11 October 2016 as Manuscript ERC-16-0427 1 Pushing estrogen receptor around in breast cancer 2 3 Elgene Lim 1,♯, Gerard Tarulli 2,♯, Neil Portman 1, Theresa E Hickey 2, Wayne D Tilley 4 2,♯,*, Carlo Palmieri 3,♯,* 5 6 1Garvan Institute of Medical Research and St Vincent’s Hospital, University of New 7 South Wales, NSW, Australia. 2Dame Roma Mitchell Cancer Research Laboratories 8 and Adelaide Prostate Cancer Research Centre, University of Adelaide, SA, 9 Australia. 3Institute of Translational Medicine, University of Liverpool, Clatterbridge 10 Cancer Centre, NHS Foundation Trust, and Royal Liverpool University Hospital, 11 Liverpool, UK. 12 13 ♯These authors contributed equally. *To whom correspondence should be addressed: 14 [email protected] or [email protected] 15 16 Short title: Pushing ER around in Breast Cancer 17 18 Keywords: Estrogen Receptor; Endocrine Therapy; Endocrine Resistance; Breast 19 Cancer; Progesterone receptor; Androgen receptor; 20 21 Word Count: 5620 1 Copyright © 2016 by the Society for Endocrinology. Page 2 of 55 22 Abstract 23 The Estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) 24 that is expressed in approximately 75% of breast cancers. Therapies that modulate 25 ER action have substantially improved the survival of patients with ER-positive breast 26 cancer, but resistance to treatment still remains a major clinical problem. Treating 27 resistant breast cancer requires co-targeting of ER and alternate signalling pathways 28 that contribute to resistance to improve the efficacy and benefit of currently available 29 treatments.
    [Show full text]
  • Supplemental Table
    Supplementary Information DMD-AR-2020-000131 Evaluation of the disconnect between hepatocyte and microsome intrinsic clearance and in vitro in vivo extrapolation performance. Beth Williamson, Stephanie Harlfinger, Dermot F McGinnity Drug Metabolism and Pharmacokinetics, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK. Table S1. Compound physicochemical properties and in vitro ADME data. ACD ACD ACD Human Hep CLint Human Mic CLint Human Main Name MW Ion Class HBD HBA TPSA LogD 6 fuinc pKa A1 pKa B1 LogP (µL/min/x10 ) (µL/min/mg) fup isoform Chlorpromazine 318.9 Base 2 32 9.6 3.4 5.4 20 39 0.060 0.026 CYP2D6 Prochlorperazine 374.0 Base 3 35 7.7 3.6 4.8 12 2 0.023 0.141 CYP2D6 Dipyridamole 504.6 Neutral 4 12 145 6.5 3.8 0.3 28 96 0.407 0.048 UGT Erlotinib 393.4 Neutral 1 7 75 5.5 3.3 3.0 5 20 0.504 0.052 CYP3A Promethazine 284.4 Base 2 32 9.1 2.8 4.6 9 1 0.144 0.090 CYP2D6 Propranolol 259.4 Base 2 3 41 9.5 1.3 3.3 10 29 0.467 0.243 CYP2D6 Rosiglitazone 357.4 Neutral 1 5 97 6.3 6.5 2.5 2.8 13 37 0.514 0.003 Other Ondansetron 293.4 Base 4 40 6.8 1.6 2.8 3 8 0.842 0.435 CYP3A Amsacrine 393.5 Neutral 2 5 89 8.2 3.1 3.2 11 40 0.434 0.007 CYP1A Antazoline 265.4 Base 1 3 28 10.3 1.4 3.6 52 195 0.726 0.562 CYP3A Gefitinib 446.9 Base 1 7 69 7.0 3.7 3.7 4 44 0.214 0.035 CYP3A Edaravone 174.2 Neutral 1 3 33 2.7 0.5 1.1 2 65 0.828 0.001 UGT Semaxanib 238.3 Neutral 2 2 45 13.2 1.5 3.4 3.0 28 68 0.036 0.031 CYP3A Verapamil 454.6 Base 6 64 8.1 2.6 4.0 23 180 0.548 0.155 CYP3A Imatinib 493.6 Base 2 7 86 13.3 7.6 2.5 3.1 3 35 0.405
    [Show full text]
  • Genome-Wide Identification of Brain Mirnas in Response to High
    Zhao et al. BMC Molecular Biol (2019) 20:3 https://doi.org/10.1186/s12867-019-0120-4 BMC Molecular Biology RESEARCH ARTICLE Open Access Genome‑wide identifcation of brain miRNAs in response to high‑intensity intermittent swimming training in Rattus norvegicus by deep sequencing Yanhong Zhao1*†, Anmin Zhang2,3*†, Yanfang Wang4, Shuping Hu3, Ruiping Zhang2 and Shuaiwei Qian2 Abstract Background: Physical exercise can improve brain function by altering brain gene expression. The expression mecha- nisms underlying the brain’s response to exercise still remain unknown. miRNAs as vital regulators of gene expres- sion may be involved in regulation of brain genes in response to exercise. However, as yet, very little is known about exercise-responsive miRNAs in brain. Results: We constructed two comparative small RNA libraries of rat brain from a high-intensity intermittent swim- ming training (HIST) group and a normal control (NC) group. Using deep sequencing and bioinformatics analysis, we identifed 2109 (1700 from HIST, 1691 from NC) known and 55 (50 from HIST, 28 from NC) novel candidate miRNAs. Among them, 34 miRNAs were identifed as signifcantly diferentially expressed in response to HIST, 16 were up- regulated and 18 were down-regulated. The results showed that all members of mir-200 family were strongly up- regulated, implying mir-200 family may play very important roles in HIST response mechanisms of rat brain. A total of 955 potential target genes of these 34 exercise-responsive miRNAs were identifed from rat genes. Most of them are directly involved in the development and regulatory function of brain or nerve.
    [Show full text]
  • Effect of Tamoxifen Or Anastrozole on Steroid Sulfatase Activity and Serum Androgen Concentrations in Postmenopausal Women with Breast Cancer
    ANTICANCER RESEARCH 31: 1367-1372 (2011) Effect of Tamoxifen or Anastrozole on Steroid Sulfatase Activity and Serum Androgen Concentrations in Postmenopausal Women with Breast Cancer S.J. STANWAY1, C. PALMIERI2, F.Z. STANCZYK3, E.J. FOLKERD4, M. DOWSETT4, R. WARD2, R.C. COOMBES2, M.J. REED1† and A. PUROHIT1 1Oncology Drug Discovery Group, Section of Investigative Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, U.K.; 2Cancer Research UK Laboratories, Department of Oncology, Hammersmith Hospital, London W12 0NN, U.K.; 3Reproductive Endocrine Research Laboratory, University of Southern California, Keck School of Medicine, Women’s and Children’s Hospital, Los Angeles, CA, U.S.A.; 4Department of Biochemistry, Royal Marsden Hospital, London, SW3 6JJ, U.K. Abstract. Background: In postmenopausal women sulfate and dehydroepiandrosterone levels. Results: Neither estrogens can be formed by the aromatase pathway, which anastrozole nor tamoxifen had any significant effect on STS gives rise to estrone, and the steroid sulfatase (STS) route activity as measured in PBLs. Anastrozole did not affect which can result in the formation of estrogens and serum androstenediol concentrations. Conclusion: androstenediol, a steroid with potent estrogenic properties. Anastrozole and tamoxifen did not inhibit STS activity and Aromatase inhibitors, such as anastrozole, are now in serum androstenediol concentrations were not reduced by clinical use whereas STS inhibitors, such as STX64, are still aromatase inhibition. As androstenediol has estrogenic undergoing clinical evaluation. STX64 was recently shown properties, it is possible that the combination of an to block STS activity and reduce serum androstenediol aromatase inhibitor and STS inhibitor may give a therapeutic concentrations in postmenopausal women with breast cancer.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • Growth Cone Responses to Growth and Chemotropic Factors
    European Journal of Neuroscience European Journal of Neuroscience, Vol. 28, pp. 268–278, 2008 doi:10.1111/j.1460-9568.2008.06327.x Growth cone responses to growth and chemotropic factors Staci D. Sanford,1 Jesse C. Gatlin,1,* Tomas Ho¨kfelt2 and Karl H. Pfenninger1 1Departments of Pediatrics, and of Cell and Developmental Biology, and Neuroscience Program, University of Colorado School of Medicine, and University of Colorado Cancer Center, Aurora, CO 80045, USA 2Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden Keywords: attractants, axonal pathfinding, growth cone, growth promotion, neuropeptides, repellents Abstract During nervous system development axons reach their target areas under the influence of numerous guidance cues that affect rate and direction of growth. This report addresses the unsettled question of whether and to what extent growth velocity and turning responses (attraction, repulsion) are interdependent. We exposed individual growth cones of fetal rat dorsal root ganglion neurons in culture asymmetrically to gradients of seven different factors and recorded their growth rates and turning angles. Growth cones exhibited divergent patterns of turning and growth responses. For example, hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1) and thrombin all promoted growth, but HGF was a powerful attractant, thrombin a potent repellent and IGF-1 did not elicit turning. Galanin and neuropeptide Y also affected growth and ⁄ or turning differentially. Finally, nerve growth factor in the culture
    [Show full text]
  • Tyrosine Kinase Inhibitors Or ALK Inhibitors for the First Line Treatment of Non-Small Cell Lung Cancer
    Tyrosine kinase inhibitors or ALK inhibitors for the first line treatment of Non-small cell lung cancer This application seeks the addition of tyrosine kinase inhibitor erlotinib (representative of class) and gefitinib and afatinib (alternatives) as well as ALK-inhibitor crizotinib to the list of the Essential Medicines List for the treatment of non-small cell lung cancer. Introduction In 2013, there were approximately 1.8 million incident lung cancer cases diagnosed worldwide and approximately 1.6 million deaths from the disease (1). Lung cancer had the second highest absolute incidence globally after breast cancer, and in 93 countries was the leading cause of death from malignant disease, accounting for one fifth of the total global burden of disability- adjusted life years from cancer. Men were more likely to develop lung cancer than women, with 1 in 18 men and 1 in 51 women being diagnosed between birth and age 79 years (1). Non-small cell lung cancer (NSCLC) is the most common form of the disease, accounting for 85–90% of all lung cancers (2)(43). For patients with resectable disease, adjuvant chemotherapy improves the absolute 5-year survival rates in Stage II and III NSCLC (9,13,65,44-47). Acceptable adjuvant chemotherapy options include etoposide/cisplatin, docetaxel/cisplatin, gemcitabine/cisplatin, pemetrexed/cisplatin, and carboplatin/paclitaxel for patients with comorbidities or unable to tolerate cisplatin. In patients with non-metastatic but inoperable NSCLC or Stage III disease, concurrent chemoradiotherapy has been shown to improve overall survival (OS) and median survival (47-53). However, most patients with NSCLC present with advanced stage disease – stage IV in particular – and half of all patients treated initially for potentially curable early-stage disease will experience recurrences with metastatic disease (3).
    [Show full text]