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Publisher: Oxford University Press   (Total: 392 journals)

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Showing 1 - 200 of 392 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 8, SJR: 0.111, h-index: 4)
Advances in Nutrition     Hybrid Journal   (Followers: 42, SJR: 2.075, h-index: 36)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 65, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 86, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 18, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 145, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 40, SJR: 1.441, h-index: 77)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 146, SJR: 3.771, h-index: 262)
American J. of Epidemiology     Hybrid Journal   (Followers: 169, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 25, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 18)
American J. of Legal History     Full-text available via subscription   (Followers: 8, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 27, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 15, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 21)
Animal Frontiers     Hybrid Journal  
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 14, SJR: 2.112, h-index: 98)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 29, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 48, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 8, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal  
AoB Plants     Open Access   (Followers: 4, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 17, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 55, SJR: 1.749, h-index: 63)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 0.779, h-index: 11)
Arbitration Intl.     Full-text available via subscription   (Followers: 19)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 13)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 30, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 3, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 42, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 51, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 285, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.646, h-index: 149)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 30, SJR: 2.374, h-index: 154)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.213, h-index: 9)
Biostatistics     Hybrid Journal   (Followers: 17, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 162, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 64, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 68, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 44, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 33, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 26, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 584, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 86, SJR: 0.771, h-index: 53)
British Medical Bulletin     Hybrid Journal   (Followers: 7, SJR: 1.391, h-index: 84)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 30)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 4, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 61, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 9, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 9, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal   (Followers: 2)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 12, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 44, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 17, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 5, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 4)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 22, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 8, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 10, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 25, SJR: 0.1, h-index: 3)
Clean Energy     Open Access  
Clinical Infectious Diseases     Hybrid Journal   (Followers: 62, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 3, SJR: 0.338, h-index: 19)
Communication Theory     Hybrid Journal   (Followers: 20, SJR: 2.62, h-index: 53)
Communication, Culture & Critique     Hybrid Journal   (Followers: 25)
Community Development J.     Hybrid Journal   (Followers: 27, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 9, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 5, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access  
Current Legal Problems     Hybrid Journal   (Followers: 27)
Current Zoology     Full-text available via subscription   (Followers: 1, SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 8, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 13)
Diplomatic History     Hybrid Journal   (Followers: 19, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 5, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 3)
Early Music     Hybrid Journal   (Followers: 15, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 39, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 51, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 14, SJR: 0.144, h-index: 3)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.791, h-index: 66)
Environmental Epigenetics     Open Access   (Followers: 3)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 16, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 54, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 8, SJR: 2.044, h-index: 58)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 1)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. Supplements     Hybrid Journal   (Followers: 7, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 9, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 174, SJR: 0.722, h-index: 38)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.09, h-index: 60)
European J. of Public Health     Hybrid Journal   (Followers: 20, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 9, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 28, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 40, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 10)
Family Practice     Hybrid Journal   (Followers: 14, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 10, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 22, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 27, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 14, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 23, SJR: 0.859, h-index: 10)
Forest Science     Hybrid Journal   (Followers: 4, SJR: 0.872, h-index: 59)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 14, SJR: 0.903, h-index: 44)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.108, h-index: 6)
French History     Hybrid Journal   (Followers: 32, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 20, SJR: 0.119, h-index: 7)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.102, h-index: 3)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 11, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 33, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 22, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 54, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 13, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 24, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 21, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 28, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 26, SJR: 0.115, h-index: 13)
Human Communication Research     Hybrid Journal   (Followers: 13, SJR: 2.199, h-index: 61)
Human Molecular Genetics     Hybrid Journal   (Followers: 8, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 72, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 16, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 60, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 51, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 12)
ILAR J.     Hybrid Journal   (Followers: 2, SJR: 1.099, h-index: 51)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.329, h-index: 26)
IMA J. of Management Mathematics     Hybrid Journal   (SJR: 0.351, h-index: 20)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.661, h-index: 28)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 2.032, h-index: 44)
Industrial and Corporate Change     Hybrid Journal   (Followers: 10, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 34, SJR: 0.184, h-index: 15)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 42, SJR: 1.994, h-index: 107)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 7, SJR: 1.911, h-index: 90)
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.529, h-index: 59)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 6, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 56, SJR: 1.264, h-index: 53)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 30)
Intl. Health     Hybrid Journal   (Followers: 5, SJR: 0.835, h-index: 15)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 1.613, h-index: 111)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 34, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 63, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 186, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 30, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 10, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 9, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 35, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 12, SJR: 0.833, h-index: 12)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.052, h-index: 42)
Intl. Political Sociology     Hybrid Journal   (Followers: 35, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 22, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 42, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 20, SJR: 0.783, h-index: 38)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1, SJR: 0.155, h-index: 4)
ITNOW     Hybrid Journal   (Followers: 1, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 15, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 45, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 13, SJR: 1.038, h-index: 60)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 14, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 4, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 41, SJR: 1.341, h-index: 96)
J. of Burn Care & Research     Hybrid Journal   (Followers: 9, SJR: 0.713, h-index: 57)
J. of Chromatographic Science     Hybrid Journal   (Followers: 18, SJR: 0.448, h-index: 42)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.167, h-index: 11)
J. of Communication     Hybrid Journal   (Followers: 50, SJR: 3.327, h-index: 82)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 35, SJR: 0.442, h-index: 16)
J. of Complex Networks     Hybrid Journal   (Followers: 1, SJR: 1.165, h-index: 5)
J. of Computer-Mediated Communication     Open Access   (Followers: 26, SJR: 2.878, h-index: 80)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 13, SJR: 0.196, h-index: 15)
J. of Consumer Research     Full-text available via subscription   (Followers: 41, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 9, SJR: 1.543, h-index: 37)
J. of Cybersecurity     Hybrid Journal   (Followers: 3)
J. of Deaf Studies and Deaf Education     Hybrid Journal   (Followers: 8, SJR: 0.69, h-index: 36)

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Journal Cover Annals of Oncology
  [SJR: 4.362]   [H-I: 173]   [48 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0923-7534 - ISSN (Online) 1569-8041
   Published by Oxford University Press Homepage  [392 journals]
  • 100PAntitumor effect of dendritic cells loaded with Fe2O3 magnetic
           nanocomplex in mice with sarcoma 37
    • Authors: Inomistova M; Khranovska N, Skachkova O, et al.
      Abstract: Background: Increasing the target delivery of generated dendritic cells (DCs) to the lymphoid tissue of the recipient can significantly improve the efficiency of immunotherapy. This can be achieved by using iron oxide nanoparticles under the action of a magnetic field – a magnetic nanocomplex (MNC).
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.048
       
  • 101PDelivery of E-cadherin (CDH1) gene and epidermal growth factor
           receptor (EGFR) siRNA, using carbonate apatite as a promising vehicle in
           treatment of breast cancer
    • Authors: Ashaie M; Othman I, Tha K, et al.
      Abstract: Background: E-cadherin (CDH1), a cell adhesion glycoprotein is widely associated with breast cancer where it is involved in tumor growth, invasion and metastasis. Down regulation of its gene is hall mark for epithelial-mesenchymal transition, which is an essential process for tumor metastasis. While various pathways are associated with E-cadherin, one of the prominent signaling pathways is via epidermal growth factor reception (EGFR), which is found to be over expressed. Silencing the over expressed EGFR gene by using a specific short-interfering RNA (siRNA), or inducing the expression of CDH1 gene with the help of a plasmid could improve management of malignant cancers by disturbing cancer cell interactions with adjacent cells and extracellular matrix; however, tumor-targeted delivery of these complexes is a major challenge in cancer therapy. This could be overcome by using pH-sensitive carbonate apatite nanoparticles that can enhance the intracellular delivery and release of the bound DNA or siRNA from endosomes to cytosol, after being transported to the tumor.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.049
       
  • 102PFunctional characterization of mammagliobin-1 isoform in breast cancer
    • Authors: Guerrette R; Robichaud G.
      Abstract: Background: Since 2007, oncologists have been using the GeneSearchTM Breast Lymph Node (BLN) Assay for the detection of metastatic breast cancer. This test detects the presence of Mammaglobin-1 (MGB1) expression in lymph nodes of breast cancer patients. Although MGB1 is overexpressed in 90% of breast cancers, its aberrant expression and function in breast cancer tissue is still misunderstood. We have recently reported the first evidence for MGB1 as potent induction of breast cancer malignancy and disease progression. More precisely, loss of MGB1 expression correlates with a decrease of cell proliferation, spheroid formation, migration, and invasion capacities of breast cancer cells. Concomitantly, we also show that MGB1 expression activates pro-malignant signaling cascades leading to epithelial to mesenchymal transitioning (EMT). More interestingly, we have also discovered new MGB1 gene products that result from transcript editing. The objective of this research is to elucidate the role of MGB1 gene products in breast cancer, we set out to investigate and characterize MGB1 isoforms in breast cancer cell processes.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.050
       
  • 103PAfatinib is active in osteosarcoma in vitro models
    • Authors: Cruz Ramos M; Zamudio-Cuevas Y, Martínez-Flores K, et al.
      Abstract: Background: Osteosarcoma is the most common bone tumour and affects younger patients. The combination of chemotherapy with aggressive surgical resection results in survival rates achieving 60%-70% in patients with localized disease. Unfortunately, 30% of osteosarcoma patients present metastatic disease at diagnosis and only 20-30% will become long-term survivors. Therefore, finding new drugs to treat these patients is a research priority. Preclinical and clinical studies suggest involvement of ErbB network aberrations in the aetiology of osteosarcomas. The present study assessed the effect of Afatinib, an irreversible ErbB family blocker, in osteosarcoma cell lines.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.051
       
  • 104PAugmentation of NAD+ levels by enzymatic action of NAD(P)H quinone
           oxidoreductase 1 attenuates adriamycin-induced cardiomyopathy
    • Authors: Khadka D; Oh G, Kim H, et al.
      Abstract: Background: Adriamycin (ADR) is a potent anticancer drug widely used to treat a variety of human neoplasms. However, its clinical use is hampered because of severe side effects such as cardiotoxicity and heart failure. ADR-induced cardiomyopathy (AIC) has been reported to be caused by myocardial damage and dysfunction through oxidative stress, DNA damage, and inflammatory responses. Nevertheless, the remedy for ADR cardiomyopathy is still not developed. We describe the effect of NAD+/NADH modulation by NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action on AIC.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.052
       
  • 105PTargeted delivery of albumin-binding caspase-3 cleavable docetaxel
           prodrug to radiation exposed local tumor
    • Authors: Cho Y; Kim H, Byun Y.
      Abstract: Background: Targeted delivery of therapeutic agent meets with hurdle of finding target ligand or receptor those are expressed tumor cells in homogenous patterns but not on normal cells. Apoptosis is an event that is programmed in all cells exposed to specific stimuli and this phenotypic event does not vary in patient to patient. In attempt to overcome limitations of conventional targeted therapy, radiation-induced apoptosis-targeted chemotherapy (RIATC) was suggested in our previous study. Caspase-3 cleavable docetaxel prodrug is treated following local administration of low dose radiation in tumor site which induces apoptosis. After initial activation of the prodrug, in-situ amplification of prodrug from expressed caspase-3 boost further activation of the prodrug.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.053
       
  • 106PAntiproliferative effect of trastuzumab and nimotuzumab with EGF on
           breast cancer cells MCF-7
    • Authors: Nikulina V; Garmanchuk L, Nikolaienko T.
      Abstract: Background: In this study, we addressed antiproliferative effects of trastuzumab (Herceptin®) and nimotuzumab (Theraloc®) in a combined application with EGF on MCF-7 cells. The epidermal growth factor (EGF) receptors have been found to be implicated in the ontology and maintenance of tumor tissues, which has fostered the discovery and development of molecularly targeted anti-EGF-receptor therapies. However, the accessibility of chemotherapeutic preparations and humanized antibodies to tumor cells in the G0 phase of the cell cycle is lower than to the cells of theproliferative pool. Given this, antitumor efficiency can potentially be enhanced by synchronizing cells in the proliferative pool. To explore this opportunity, we added EGF to tumor cells in combination with nimotuzumab and trastuzumab (antibodies against EGF-R typeI and II, respectively).
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.054
       
  • 108PThe role of citrus peel extract in inhibiting progression and
           recurrence of prostate cancer
    • Authors: Shammugasamy B; Valtchev P, Dehghani F, et al.
      Abstract: Background: Prostate cancer (PC) is one of the leading cause of cancer related deaths in men. PC progression and recurrence following initial treatments possesses mortality threat amongst these patients. Cell cycle re-entry of quiescent cancer cells has been suggested for cancer progression and recurrence. The slow progression of PC allows a window of opportunity for intervention through diet. An inverse association of flavonoids intake and PC development has been demonstrated in epidemiological studies. We hypothesized that citrus peel that is rich in various bioactive compounds including flavonoids may impede cell cycle re-entry by quiescent PC cells.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.055
       
  • 109PMultiphysics modelling of alpha-immuno-conjugate delivery and
           background dose
    • Authors: Liu T.
      Abstract: Background: Radiotherapy is one of the commonly used approaches to treat cancer. The research trend and breakthroughs in radiotherapy is focusing on the high linear energy transfer (LET) radiation like the alpha particles. Thus, the alpha particles based method is an important option of radiotherapy development, and Targeted Alpha Therapy (TAT) is the most important application of using alpha particles in the past decade. This paper highlights the research work done on computational modelling of TAT at Canadian Nuclear Laboratories (CNL).
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.056
       
  • 110PCellMiner and CellMiner cross-database (CDB): Resources for the
           exploration of pharmacogenomics using cancerous cell-lines
    • Authors: Reinhold W; Pommier Y.
      Abstract: Background: Determining the influence of molecular alterations on pharmacological responses in cancer cell lines from the omic perspective is the logical first step towards making oncology treatment for patients more effective, specific, and targeted. Our established CellMiner (and in development CellMinerCDB (https://discover.nci.nih.gov/cellminercdb/) web-applications provide high-quality, clean, and numerically extensive molecular and pharmacological data for these purposes.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.057
       
  • 111PEffect of IFNα-2b on migrational ability of tumor cells on early
           stages of breast cancer development
    • Authors: Herheliuk T; Perepelytsina O, Ostapchenko L, et al.
      Abstract: Background: Inflammatory reactions play an important role in all stages of tumor development. A shift to the mesenchymal phenotype causes an increase of migratory capacity of tumor cells. Epithelial-mesenchymal transition (EMT) can also be caused by local inflammation. Searching for factors that can inhibit the transition of the cell population from the epithelial to the mesenchymal phenotype is very important for antitumor therapy. Interferon alfa (IFNα-2b) can be such a factor that has a direct effect on proliferation, differentiation and migration of tumor cells. The aim of this study was to compare the effect of IFNα-2b on the expression of EMT markers and on the basic cellular processes on 2D and 3D growth models.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.058
       
  • 112PCombination effects of MEK inhibitors with statins on cancer cells
    • Authors: Iizuka-Ohashi M; Watanabe M, Taguchi T, et al.
      Abstract: Background: With increasing clinical demands for MEK inhibitors in cancer treatment, overcoming the resistance to MEK inhibitors is becoming an important issue. Especially, the activation of PI3K-Akt pathway is well known to impede the sensitivity to MEK inhibitors. Indeed, a number of early-phase clinical studies, which test the combination efficacy of MEK and PI3K dual inhibition, have been performed; however, the results of these studies remain unsatisfactory. Thus, feasible combination therapies with MEK inhibitors are required to inhibit PI3K-Akt signaling. Mavalonate pathway is not only essential for cholesterol synthesis but also crucial for cell survival with prenylation of small GTPases, which are the upstreams of PI3K-Akt pathway. We thus hypothesized that the blockage of mevalonate pathway using the cholesterol-lowering drugs statins could enhance the efficacy of MEK inhibitors.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.059
       
  • 114PImpact by age on dose-limiting toxicities in phase 1 oncology trials
           of cytotoxic agents and molecular targeted agents
    • Authors: Ebata T; Shimomura A, Koyama T, et al.
      Abstract: Background: Elderly cancer patients aged 65 or more are generally frail compared with younger patients. They are considered to be the age group of less fitting for clinical trials, especially investigating feasibility. For the past decade, the types of the agents have been changing and the number of drug classes has been increasing. The aim of our study was to investigate the impact by age on dose-limiting toxicities (DLT) in each type of agents.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.061
       
  • 115PSequencing of cancer panels through “next generation sequencing”
           (NGS) in the clinical practice of a phase 1 trial unit
    • Authors: Wiermann A; Boni V, de Miguel M, et al.
      Abstract: Background: The fundamental principle of precision oncology is the correspondence of molecular, genomic and clinical data with the underlying mechanisms of specific therapeutic agents in order to provide more effective and rational cancer treatment strategies.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.062
       
  • 116PA targeted genomic analysis uncovered a large spectrum of acquired
           resistance mechanisms to BRAF inhibitor therapy in metastatic melanoma
           patients
    • Authors: Louveau B; Reger de Moura C, Battistella M, et al.
      Abstract: Background: Several mechanisms have been described to explain the emergence of acquired resistance to MAPK inhibitors. Using tumor DNA sequencing, genetic alterations activating the MAPK and the PI3K/AKT pathways have been associated to emergence of resistance mechanisms. Studies focusing on targeted mRNA analysis have associated gene expression alterations to resistance. Nevertheless, resistance to BRAF inhibitors (BRAFi) remained unexplained for nearly half of melanomas highlighting the need of an approach to exhaustively characterize resistance mechanisms to such therapies.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.063
       
  • 117PExternal validation of the Gustave Roussy immune score (GRIm score) in
           an unselected cohort of patients treated at the Clinica Universidad de
           Navarra
    • Authors: Ceniceros L; Gardeazabal I, Rodriguez M, et al.
      Abstract: Background: The proper selection of patients in phase I studies is crucial in order to guarantee not only a safer approach to patients but also to obtain reliable results. Recently, Gustave Roussy Immune Score (GRIm-score) predicted overall survival for patients involved in phase I immune-oncology (IO) trials in a more accurate way when compared to other classical scores. The goal of our study is to validate the GRIm-score in our institution.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.064
       
  • 118PPrecision trial designer-web: A web-based app to assist in the design
           of genomics-driven trials
    • Authors: Mazzarella L; Melloni G, Guida A, et al.
      Abstract: Background: Genetic biomarker-driven trials are powerful ways to test targeted drugs, but are often complicated by the rarity of the biomarker-positive population. “Umbrella” trials circumvent this issue by testing multiple hypotheses to maximize accrual. However, allocation strategy (ie which drug to administer first, in case multiple actionable mutations coexist) greatly affects sample size and should be carefully planned based on relative mutation frequencies. Inadequate planning results in lack of statistical power and inconclusive trials. The bigger the trial, the higher the chance of conflicting drug allocation. Biomarker-based trial design may be facilitated by leveraging data from public sequencing projects, but no specific computational tool is available.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.065
       
  • 119PAdjuvant radiation therapy effects systemic immune response cells in
           female breast cancer patients
    • Authors: Lewin N.
      Abstract: Background: Radiation induces DNA damage, leads to cell cycle arrest and cell death. We investigated the effect of adjuvant radiation therapy (RT) on systemic innate and adaptive immune cells in female breast cancer (BC) patients by assessing circulating white blood cells (WBCs) and its subpopulations.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.066
       
  • 120PComparison of model-based dose escalation design with rule-based
           design of phase I oncology trials
    • Authors: Shimomura A; Ebata T, Koyama T, et al.
      Abstract: Background: To improve efficiency and safety of phase I trials, various new designs have been proposed. We reported that rule-based design and model-based design were similar profile in efficiency and safety (Shimomura A, et al. TAT 2017). The limitation of the study was retrospective single institutional study. Then, we investigated the literature or presentation based analysis to compare model-based design with rule-based design of phase I trials.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.067
       
  • 121PReal-life tolerance and plasma exposure assessment of lenvatinib in
           thyroid metastatic cancer patients
    • Authors: Goldwirt L; Madelain V, Chougnet C, et al.
      Abstract: Background: Lenvatinib (LenvimaTM, LVT), an oral tyrosine kinase inhibitor, has shown efficacy in iodine-131–refractory thyroid cancer with a median progression free survival (PFS) in the LVT 24 mg daily arm of 18.3 months compared to 3.6 months in the placebo arm. Yet, with a 97.3% incidence of all grades treatment-related adverse effects, dose interruption or dose reduction occur at 82.4% and 67.8%, respectively. The objective of this study was to assess real-life tolerance and LVT plasma exposure after dose reduction in thyroid cancer patients.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.068
       
  • 122PSelecting patients with metastatic colorectal cancer for treatment
           with temozolomide using proteomic analysis of MGMT
    • Authors: Cecchi F.
      Abstract: Background: Temozolomide (TMZ) is a standard treatment for melanoma and glioblastoma and it has shown limited but encouraging activity in patients with metastatic colorectal cancer (mCRC). In multiple cancer types, tumor expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a marker of poor response to TMZ. MGMT promoter methylation is associated with loss of MGMT expression and response to TMZ. We hypothesized that mCRC patients whose tumors expressed quantities of MGMT protein below a pre-defined cutoff would have better outcomes on TMZ than patients with MGMT expression above the cutoff. To test our hypothesis, we assessed MGMT by mass spectrometry in the tumor samples of patients with refractory mCRC and MGMT promoter methylation who had received TMZ.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.069
       
  • 123PPrediction of response to trasutuzumab/pertuzumab/taxane therapy by
           microRNA in HER2 positive advanced breast cancer
    • Authors: Kawachi A; Shimomura A, Matsuzaki J, et al.
      Abstract: Background: First line standard treatment for advanced HER2-positive breast cancer is trastuzumab/pertuzumab/docetaxel (HPT). HPT therapy has shown significant response rates and prolonged overall survival compared with single anti-HER2 antibody containing therapy. However, some patients with HER2-overexpressing breast cancer show primary resistance to HPT therapy. There is no predictive marker to identify response to HPT therapy. Therefore, we explored the combination of microRNA (miRNA) that is associated with response to HPT therapy.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.070
       
  • 124PDetection of KRAS mutation, MSI and TP53 status in Indonesian CRC
           patients with its association to PD-L1 expression
    • Authors: Kusumo G; Putra T, Budiyati A, et al.
      Abstract: Background: KRAS and microsatellite instability (MSI) status are well established markers in personalized therapy of colorectal cancer (CRC). The immune checkpoint inhibitor Programmed Death 1 (PD1) and its ligand (PD-L1) have been reported in recent studies as promising targets for cancer therapy. However, there is still a debatable result in the correlation between PD1/PD-L1 expression and KRAS and MSI status as the essential CRC biomarker. Therefore, this study aims to characterize molecular profiles of KRAS, MSI, and TP53 in their association with PD-L1 expression in an Indonesian CRC patient cohort.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.071
       
  • 125PComparison of different testing methods for detection of BRAF V600
           mutation in metastatic melanoma
    • Authors: Hernandez-Losa J; Ruano Y, Trigo Sanchez I, et al.
      Abstract: Background: Cobas® 4800 BRAF V600 Mutation Test is a CE-marked and FDA-approved in vitro diagnostic assay used to detect metastatic melanoma patients eligible for treatment with BRAF inhibitors. The aim of the study is to compare the performance of two additional commercial kits to assess BRAF mutations in this context
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.072
       
  • 126PAssessment of genetic polymorphisms of CXCR5 on response to therapy of
           non-Hodgkin lymphoma (NHL)
    • Authors: Hashem T; Elmasry M, Makhlouf M.
      Abstract: Background: The chemokine receptor CXCR5 is selectively expressed on B cells and it is involved in lymphocyte homing and the development of normal lymphoid tissue. Its principle ligand is CXCL13 or B lymphocyte chemoattractant (BLC). Three polymorphisms in CXCR5 gene, rs148351692C/G, rs6421571C/T, and rs78440425G/A, have been identified in CXCR5 gene. The aim of the work is to study the detection and to assess the impact of genetic polymorphisms of CXCR5 on the susceptibility and response to therapy of non-Hodgkin lymphoma (NHL).
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.073
       
  • 127PStudies on the carcinogenic mechanisms of Growth Receptor Bound
           Protein 7 in breast cancer cells and its clinical therapeutic applications
           
    • Authors: Chen L.
      Abstract: Background: Growth factor receptor bound protein 7 (GRB7) is a member of Grb family, and it is an adaptor protein. GRB7 has five functional domains, participated in many different signaling pathway.Human epidermal growth factor receptor 2 (HER2) is classified as a subtype in breast cancer. Studies until now have indicated that GRB7 and HER2 are highly correlated.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.074
       
  • 128PErythromycin readthrough of APC nonsense stop codon mutation in
           Familial adenomatous polyposis
    • Authors: Kariv R; Fliss-Isacov N, Caspi M, et al.
      Abstract: Background: Read-through of genetic nonsense mutations has been proven effective in mice models and for some human clinical conditions and can lead to the expression of a full-length protein. Based on initial work that showed aminoglycoside and macrolide antibiotics can read-through adenomatous polyposis coli (APC) nonsense mutations, we have initiated a clinical trial for erythromycin treatment in familial polyposis (FAP) patients that result from nonsense mutations in the APC gene.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.075
       
  • 129PIdentification of chromosomal aberrations using fluorescence in situ
           hybridization (fish) in bladder cancer patients of south Indian region
    • Authors: Kovendan K; Meyyalazhagan A, Jebanesan A, et al.
      Abstract: Background: Bladder cancer is a heterogeneous malignancy with wide scale of clinical manifestation. Different chromosomal aberrations have been already identified in bladder tumors. Older age, Asian ancestry and a positive family history of bladder cancer have long been recognized as important risk factors. The aim of the present investigation was to study the major chromosomal aberrations (CA) like deletion, translocation, inversion and mosaic in bladder cancer patients of Tamil Nadu, Southern India.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.076
       
  • 12INGenomic-guided drug discovery: IDH inhibitors - From bench to bedside
    • Authors: Schenkein D.
      Abstract: Mutations in isocitrate dehydrogenase (IDH)1 or IDH2 are seen in ∼15–20% of patients with acute myeloid leukemia (AML). Mutant IDH (mIDH) reduces α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), leading to histone hypermethylation and a block in myeloid differentiation. Ivosidenib (AG-120) and enasidenib (AG-221) are potent, selective, oral small molecule inhibitors of mIDH1 and mIDH2, respectively. Both have been shown preclinically to reduce aberrant 2-HG levels and promote myeloid differentiation, and as monotherapy are associated with robust overall response rates in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Enasidenib received full approval in the United States in Aug 2017 for the treatment of adult patients with R/R AML with an IDH2 mutation. A New Drug Application was recently submitted to the FDA for ivosidenib for the treatment of patients with R/R AML and an IDH1 mutation, based on evidence in patients showing clinical activity and observation of clinical benefit, including achievement of transfusion independence, and a decrease in the frequency of comorbidities such as febrile neutropenia and infections in responding patients. Additional data demonstrate that ivosidenib monotherapy results in deep IDH1 mutation clearance in a subset of patients with R/R AML and untreated AML who achieve clinical response. Tolerability and preliminary clinical activity data were also recently presented from two Phase 1 studies evaluating ivosidenib and enasidenib in combination with standard induction (7 + 3) chemotherapy or azacitadine in newly diagnosed AML patients. Independent clinical trials are currently underway for ivosidenib in mIDH1-positive malignancies in the solid tumor context. This presentation will focus on the discovery of these investigational medicines, as well as the promising clinical and translational results from the hematologic malignancy and solid tumor trials.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.004
       
  • 130PTo assess the pain control and tolerance to drug induced emesis in
           oral and neck carcinoma patients undergoing chemoradiation treated for
           pain relief with tapentadol (TAPAL -ER 50) vs. tramadol plus paracetamol
           with and without anti-emetic support
    • Authors: Narayanasamy R.
      Abstract: Background: Pain control in oral and neck carcinoma patients treated with chemoradiation are a challenge to manage, achieving a pain control and avoiding the complication of pain killers is as more important as pain control. In this study locally advanced squamous cell carcinoma treated with concurrent chemo radiation involving inj cisplatin for all patients and few patients were given inj nimotuzumab along with inj cisplatin. Controlling pain for moderate- severe level with tramadol without antiemetics is not tolerated by most of the patients, adding a drug for a drug induced complication (emesis) is a burden for patients, hence drug with least complication is always better.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.077
       
  • 131PIs HER2 positive disease a more aggressive breast cancer sub-type in
           young women'
    • Authors: Anghel R; Gales L, Serbanescu L, et al.
      Abstract: Background: Breast cancer is the leading cause of cancer-related deaths in women aged 45 and younger in developed countries, and although generally improving, survival rates for young women with breast cancer remain lower than for older women. The aim of the study was to evaluate the percentage and the outcome of women younger than 45 with HER2 positive disease.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.078
       
  • 132PMicroRNA dysregulation as a prognostic biomarker in wild-type
           RAS/RAF/PTEN/PI3 metastatic colon cancer treated with anti-EGFR
           therapeutics
    • Authors: Aksoy S; Kanat O, Tunca B, et al.
      Abstract: Background: Expectation of benefit from the antiepidermal growth factor receptor (anti-EGFR) therapeutics is a not yet solved question in metastatic colorectal cancer (mCC). MicroRNAs (miRNAs), which are short non-coding RNA molecules and important regulators of cell signaling pathways crucial for the growth of human cancer cells. Several studies have examined the expression profiles of miRNAs in response to different chemotherapy treatments and found that the expression patterns may be associated with the treatment response. Therefore, our aim was to evaluate the differential expression profiles of miRNAs in mCC treated with anti-EGFR therapeutics (cetuximab, panitumumab).
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.079
       
  • 133PThe global forecast of prostate cancer drug-treatable populations
           eligible for targeted anticancer therapies (2017-2027)
    • Authors: Parihar N.
      Abstract: Background: Targeted anticancer therapies have been approved by the Food and Drug Administration for use in some men with metastatic castrate-resistant prostate cancer (MCRPC). This study aimed to forecast the first-line MCRPC drug-treatable populations (DTP) by global geographic/economic regions over the period 2017-2027.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.080
       
  • 134PImpact of sorafenib on quality of life in hepatocellular carcinoma
    • Authors: Abraham A; Nair B, Anand A, et al.
      Abstract: Background: HCC is the third most common cause of cancer related mortality, globally. Although early diagnosis is associated with better prognosis. Sorafenib, an orally administered, small molecule multikinase inhibitor, has proven efficacy in advanced HCC, by targeting cellular signaling pathways that orchestrate tumor angiogenesis and proliferation via Vascular Endothelial Growth Factor Receptor(VEGFR), Platelet-Derived Growth Factor Receptor β (PDGFR-β) and Raf -1. The impact of targeted therapy on the Quality of life of cancer patients is gaining importance as these molecules have markedly improved the Overall survival and Progression free survival.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.081
       
  • 135PAxitinib: An audit of dose adjustments, tolerability and efficacy in
           advanced renal cell carcinoma
    • Authors: Parkar R; Boleti E.
      Abstract: Background: Axitinib is an oral multikinase inhibitor, which is licenced for use in advanced renal cell carcinoma after failure of prior systemic treatment. We have assessed the efficacy and general tolerability of axitinib in a real world setting and audited our local dose escalation/reduction practice.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.082
       
  • 136PDrug transporter pharmacogenetics as a predictor of
           chemotherapy-induced toxicity in lung cancer patients
    • Authors: Zair Z; Singer D.
      Abstract: Background: Lung cancer remains the commonest cancer and the most common cause of cancer-associated death worldwide. Use of chemotherapeutic drugs are significant in managing patients with lung cancer, however, due to serious adverse drug reactions (ADRs) these drugs are often underutilized. Our aim was to perform a meta-analysis and systematic review of studies looking at pharmacogenetic drug transporter variants as predictors of ADRs in lung cancer patients undergoing chemotherapy.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.083
       
  • 137PSunitinib 4:2 versus 2:1 regimen
    • Authors: Parkar R; Lytra T, Boleti E.
      Abstract: Background: In addition to auditing our local practice of prescribing sunitib, the purpose of the study was to evaluate and compare the safety, efficacy and tolerability of the 4 weeks on and 2 weeks off regime (4:2), which is currently considered to be standard of practice to the 2weeks on and 1 week off regime (2:1), in patients with metastatic renal cell carcinoma.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.084
       
  • 138PPreclinical testing of NEDD8 and proteasome inhbitors for a
           treatment-refractory, metastatic high-grade mucinous colorectal cancer
           patient
    • Authors: Torchiaro E; Petti C, Isella C, et al.
      Abstract: Background: Colorectal cancer (CRC) is the third leading cause of death in the world. CRC shows variable phenotypic make-ups; among them, a particularly aggressive histological subtype is the “high grade mucinous” (HGM) adenocarcinoma, highly mucinous, prone to metastasis and typically refractory to treatments. In some cases, HGM is accompanied by a peculiar “signet ring” phenotype of cancer cells. Early stage diagnosis of signet ring HGM is rare, clinical symptoms occur late and most cases are detected at an advanced stage, with a poor overall survival. We demonstrated that a transcriptional signature of HGM displays negative prognosis and sensitivity to the NEDD-8 inhibitor pevonedistat, suggesting the involvement of neddylation- and ubiquitination-based mechanisms in these cases.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.085
       
  • 139PHepatocellular carcinoma (HCC) treated with sorafenib (SFB) and
           hepatitis C virus (HCV) infection
    • Authors: Rocha M; Fortuna A, Castro A, et al.
      Abstract: Background: The prevalence of HCV infection in Portugal ranges between 1 and 1.5%. Treatment of HCV evolved since the advent of direct-acting antiviral agents with free globally access since 2015 in Portugal. These patients are at a high risk of developing HCC as the only approved systemic therapy is sorafenib (SFB). The aim of this work was to show the outcomes in the treatment of advanced HCC in patients infected with HCV in Centro Hospitalar Porto (CHP).
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.086
       
  • 140PThe predictive role of estrogen receptor beta (ER-β) in androgen
           receptor (AR)-positive triple-negative breast cancer (TNBC)
    • Authors: Anestis A; Mihailidou C, Theocharis S, et al.
      Abstract: Background: Androgen receptor (AR) is playing an important role in the progression of a subset of TNBC. We evaluated the impact of ERβ expression along with anti-AR drugs in AR-positive TNBC.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.087
       
  • 141PSelf-questionnaire to assess patient’s preferences for participation
           in phase I clinical trials
    • Authors: Verret B; Perret A, Delaloge S, et al.
      Abstract: Background: Patient Preference Assessment Tool (PPAT) is a patient self-assessment questionnaire designed by Emory (US) to allow easy and rapid evaluation of patient preferences for phase 1 (P1) trial participation. Beyond being a legal requirement, informed consent has a critical role to ensure that patient’s trial participation trial matches his/her expectations and understanding of treatment options. This tool has not been independently validated yet. We therefore aimed at assessing PPAT in two cohorts of P1 and phase 2-3 (P2-3) patients (pts) treated at Gustave Roussy (France).
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.088
       
  • 142PTargeted anticancer therapy and concomitant hypofractionated
           radiotherapy in breast cancer
    • Authors: Bonzano E; Guenzi M, Corvò R.
      Abstract: Background: HER-2 positive breast cancer represents 20% of breast cancers. If untreated, they have a worse prognosis than HER-2-negative tumors, but adjuvant therapy with trastuzumab (TSZ) improves survival. This treatment is usually well tolerated. The more frequent adverse event (30%) is asymptomatic decrease in left ventricular ejection fraction (LVEF), evaluated in our experience by echocardiogram at the start and the end of TSZ.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.089
       
  • 143PAurora Kinase A (AURKA) is an independent predictor of recurrence in
           breast ductal carcinoma in situ (DCIS)
    • Authors: Miligy I; Gaber A, Toss M, et al.
      Abstract: Background: Current clinical and pathological parameters are important predictors of recurrence in breast ductal carcinoma in situ (DCIS) but they are insufficient to reflect its molecular heterogeneity. Biological characterisation has the potential for individualising therapy for DCIS. Aurora Kinase A (AURKA), located on 20q13.2, shows copy number alteration in DCIS and is a key regulator of cell cycle progression. High expression of AURKA is associated with poor outcome in invasive breast cancer (IBC), however it is not confirmed in the pre-invasive stage. This study aims to assess the role of AURKA in DCIS behaviour.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.090
       
  • 144PThe role of topoisomerase II-α (TOPO IIA) as a predictive factor for
           response to neoadjuvant anthracycline-based chemotherapy in locally
           advanced breast cancer
    • Authors: Gamea M.
      Abstract: Background: Topoisomerase II-α is a molecular target of anthracyclines; several studies have suggested that topoisomerase II-α expression is related to response to anthracycline treatment. The objective of this study was to evaluate whether topoisomerase II-α overexpression predicts response to anthracycline treatment in locally advanced breast cancer patients.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.091
       
  • 145PThe clinical significance of lncRNA DANCR in upper rectal
           adenocarcinoma
    • Authors: Aksoy F; Aksoy S, Tunca B, et al.
      Abstract: Background: Long noncoding RNAs (lncRNAs) are dysregulated in many cancer types and are believed to play crucial roles in regulating several hallmarks of cancer biology. However, the clinical significance of the lncRNA DANCR in rectal cancer is unclear. This study aims to investigate the prognostic value of lncRNA DANCR in upper rectal cancer patients.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.092
       
  • 146PActivation of lung metastasis after lymph node dissection
    • Authors: Sukhbaatar A; Takahashi T, Mori S, et al.
      Abstract: Background: Lymph nodes (LNs) are an essential organ in an immune system, and lymphatic vessels connect them. Their primary function is to maintain the health of the body via filtering morbific material from the lymphatic fluid. In the case of cancer metastasis, cancer cells are disseminated from primary tumor via the bloodstream to the distant sites. Clinically, detection of metastasis within sentinel lymph node (SLNs) is significantly predictive of prognosis with implications for the patient's survival and adjuvant therapy. The limited studies available report that dissection of normal lymph nodes (LNs) is involved in the activation and rapid growth of latent tumors in distant metastasis.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.093
       
  • 147PClinicopathological significance of HER2 and EGFR expression in
           urothelial carcinoma: A single center study
    • Authors: Botiralieva G; Tillyashaykhov M, Yusupbekov A.
      Abstract: Background: Urinary bladder cancer is the ninth most common malignancy in the Uzbekistan. 94% cases of urinary bladder cancer made up urothelial carcinoma (UC). There were limited options for patients who are refractory to systemic chemotherapy. Targeted agents as EGFR/HER2 has been proved in a wide range of cancers, but no studies have yet clarified the clinicopathological significance of them in UC. The aim of this study is determination of EGFR/HER2 overexpression which would widen therapeutic options for patients with advanced UC.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.094
       
  • 16INCombining PARP inhibitors with CPI
    • Authors: Lynce F.
      Abstract: Background: Immunotherapy has shifted the treatment paradigm for many malignancies, but not all cancer types have enjoyed a clinically meaningful response from checkpoint blockade. Therefore combination therapies that allow enhancement of the antitumor immune response are needed. Poly(ADP-ribose) polymerase (PARP) inhibitors may stimulate antigen presentation via increased T cell cytotoxic activity. In preclinical models, the combination of PARP inhibition with anti-PD-L1 therapy compared with each agent alone has been shown to significantly increase the therapeutic efficacy. PARP inhibitors when combined with anti-CTLA-4 therapy in BRCA1-deficient ovarian tumor models have also been found in vitro to induce long-term survival. One group that may benefit from this approach are tumors with germline or somatic mutations in the homologous recombination (HR) DNA damage repair pathway – including BRCA1/2, PALB2, ATM, and the FANC family of genes among others. It is unclear whether this benefit can be extended to HR proficient tumors. This presentation overviews these data and ongoing clinical trials designed to answer these questions.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.022
       
  • 17INMDICT consensus report: Recommendations regarding response criteria,
           endpoints and study designs for the development of immunotherapy
           combinations
    • Authors: Seymour L; Giaccone G, Tabernero J.
      Abstract: Background: The ‘Methodology for the Development of Innovative Cancer Therapies’ (MDICT) task force was originally established in 2006 to provide practical guidance on the development of anticancer targeted agents. The task force published a number of recommendations. [1] [2] [3] [4] Although originally focused on targeted agents, for 2018, it was decided to convene the task force to examine issues in the development of immune based therapies. [1] Booth CM, Calvert AH, Giaccone G, Lobbezoo MW, Seymour LK, Eisenhauer EA. Endpoints and other considerations in phase I studies of targeted anticancer therapy: Recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies (MDICT). EJC 2008;44(1):19–24. [2] Booth CM, Calvert AH, Giaccone G, Lobbezoo MW, Eisenhauer EA, Seymour LK. Design and conduct of phase II studies of targeted anticancer therapy: Recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT). EJC 2008;44:125–9. [3] Goodwin R, Giaccone G, Calvert H, Lobbezoo M, Eisenhauer EA. Targeted agents: How to select the winners in preclinical and early clinical studies' Eur J Cancer 2012;48:2170–8. [4] Seymour LK, Calvert AH, Lobbezoo MW, Eisenhauer EA, Giaccone G. Design and conduct of early clinical studies of two or more targeted anticancer therapies: Recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.005
       
  • 18INVulnerabilities of IDH mutant gliomas
    • Authors: Cahill D.
      Abstract: Background: Approximately 80% of WHO grade II and III gliomas, and secondary glioblastomas (representing 25% of adult diffuse gliomas overall) harbor mutations in the metabolic isocitrate dehydrogenase enzymes encoded by the IDH1/2 genes. These mutations, now recognized as the genetic hallmark of these cancers, result in neomorphic enzymatic activity driving overproduction of the oncometabolite 2-hydroxyglutarate (2-HG), which leads to profound reprogramming of tumor cellular metabolism. As a result, IDH1-mutant gliomas are dependent upon the canonical coenzyme NAD+ for survival. It is known that poly(ADP-ribose) polymerase (PARP) activation consumes NAD+ during base excision repair of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD+ biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide could potentiate NAD+ depletion-mediated cytotoxicity in mutant IDH1 cancer cells.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.006
       
  • 19INMetabolic consequences of arginine deprivation in ASS1-deficient
           cancers
    • Authors: Van Tine B.
      Abstract: Background: Argininosuccinate Synthetase 1 (ASS1) is silenced in ∼90% of sarcomas. Loss of this urea cycle enzyme causes cells to become dependent upon extracellular arginine for continued cell growth and proliferation. Upon arginine starvation, ASS1(-) sarcoma cells undergo autophagy, increase their glutamine dependence and undergo growth arrest. In order to identify potentially exploitable synthetic lethal targets arising from the induction of autophagy following arginine deprivation, we investigated the metabolic alterations caused by arginine deprivation resulting from treatment with PEGylated arginine deiminase (ADI-PEG20). Mass spectroscopy was performed and revealed a significant increase in the level of serine biosynthesis from glucose which resulted from the up regulation of PHGDH. When paired with ADI-PEG20 treatment, inhibition of serine metabolism results in significant cell death. With recent studies showing the importance of serine biology in cancer, as well as recent generation of a small molecule PHGDH inhibitor to the rate limiting enzyme in serine biosynthesis, this newly identified synthetic lethality proves to be an exploitable therapeutic option for ASS1 deficient sarcomas.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.007
       
  • 1INTREX1 as a gate-keeper of cGAS/STING-mediated activation of interferon
           type I in cancer cells treated with DNA-damaging agents
    • Authors: Demaria S.
      Abstract: Background: The presence of DNA in the cytosol during viral infection elicits virus-specific immunity, a process orchestrated by the induction of interferon type I (IFN-I), which recruits and activates dendritic cells (DCs) capable of cross-priming CD8 T cell against viral antigens. Cytosolic double-stranded (ds)DNA is sensed by the cyclic GMP-AMP synthase (cGAS), which produces cGAMP and activates the downstream adaptor stimulator of IFN genes (STING) to induce IFN-I. CD8 T cells are also key anti-tumor effectors and their activation is largely dependent on the same pathways that regulate the activation of virus-specific CD8 T cells. Endogenous DNA accumulates in the cytosol of cells that harbor defects in the DNA damage repair (DDR) machinery, a common feature of neoplastic cells that can be exploited by DNA damaging chemotherapy and ionizing radiation (IR) to mimic a viral infection and activate cGAS/STING pathway in cancer cells.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046
       
  • 21INTargeting of the LXR-cholesterol axis as a metabolic co-dependency for
           brain cancers
    • Authors: Villa G.
      Abstract: Background: Oncogenic mutations in growth factor receptor signaling pathways are common in cancer, including in tumors that arise from or metastasize to the brain. However, most small-molecule inhibitors targeting growth factor receptors have failed to show efficacy for brain cancers, potentially due to inability to achieve sufficient drug levels in the central nervous system (CNS). Targeting tumor co-dependencies provides an alternative approach, particularly if drugs with high brain penetration can be identified.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.008
       
  • 24INM3814: A novel investigational DNA-PK inhibitor to target DNA double
           strand break repair
    • Authors: Zenke F.
      Abstract: Deoxyribonucleic acid-dependent protein kinase (DNA-PK) plays a critical role in the repair of DNA double strand break (DSBs). DNA double stranded breaks are the most lethal type of DNA lesion, and cells have developed two distinct repair pathways to protect the cell genome from the deleterious effect of DSBs. While homologous recombination occurs mainly during S and G2 phase and requires a homologous DNA template, non-homologous end-joining, (NEJH) uses direct ligation of DNA ends without a homologous DNA template and can therefore take place anytime during the cell cycle. DNA-PK is a key enzyme in NHEJ-mediated repair of DSBs and, therefore, represents an attractive pharmacological target. Selective inhibition of DNA-PK could synergistically enhance the activity of many commonly used DSB inducing treatment modalities, such as radiotherapy and certain chemotherapeutic agents. The presentation will provide an overview of the biological role of DNA-PK in normal and cancer cells, available pre-clinical data that explore the effect of DNA-PK inhibition in vitro and in vivo, and early data from DNA-PK inhibitors currently in clinical development.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.009
       
  • 25INThe relationship between DNA damage and immune checkpoint activation
           in cancer
    • Authors: Kennedy R.
      Abstract: Background: In cancer the presence of T cell immune infiltration has been recognised as a prognostic factor, however the mechanisms underpinning this response are not clearly defined. Our group and others have identified a relationship between type I Interferon immune signalling and loss of DNA repair, particularly the Fanconi Anemia pathway, in several different types of cancer. We therefore investigated the mechanism activating this immune response in the context of abnormal DNA repair.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.010
       
  • 26INSenescence after growth arrest: A mechanism by which CDK4/6 inhibitors
           can mediate their activity suppressing tumor progression
    • Authors: Koff A; Klein M, Dickson M, et al.
      Abstract: Background: CDK4/6 inhibitors are being used to treat a variety of human malignancies. In well-differentiated (WDLS) and dedifferentiated (DDLS) liposarcoma we had previously suggested that their clinical promise might be associated with their ability to down-regulate the MDM2 protein. In cultured cell lines, the down-regulation of MDM2, after cells left the cell cycle following CDK4 inhibition, induces them to progress from quiescence into senescence. Today, we will present further evidence supporting the idea that senescence after growth arrest is a mechanism that can account for the activity of CDK4 inhibitors, at least in WD/DDLS.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.011
       
  • 27INThe function of cyclin D-CDK4/6 kinases in cancer cell metabolism and
           anti-tumor immune surveillance
    • Authors: Sicinski P.
      Abstract: D-type cyclins (D1, D2 and D3) together with their associated cyclin-dependent kinases CDK4 and CDK6 are components of the core cell cycle machinery that drives cell proliferation. Inhibitors of CDK4 and CDK6 are currently in clinical trials for patients with several cancer types, with promising results. We demonstrated that cyclin D3-CDK6 phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. This re-directs the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumor cells reduces PPP and serine pathway flows, thereby depleting anti-oxidants NADPH and glutathione. This, in turn, elevates the levels of reactive oxygen species and causes tumor cell apoptosis. The pro-survival function of cyclin D-associated kinase operates in tumors expressing high levels of cyclin D3-CDK6 complexes. We propose that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumor subsets that undergo cell death and tumor regression upon CDK4/6-inhibition. Cyclin D3-CDK6, through its ability to link cell cycle and cell metabolism represents a particularly powerful oncogene that affects cancer cells at several levels, and this property can be exploited for anti-cancer therapy. Targeting immune checkpoints such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1 have been approved for treating multiple types of human cancers with durable clinical benefit. However, many cancer patients fail to respond to anti-PD-1/PD-L1 treatment, and the underling mechanism(s) is not well understood. Recent studies revealed that response to PD-L1 blockade might correlate with PD-L1 expression levels on tumor cells. Hence, it is important to mechanistically understand the pathways controlling PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients. We found that PD-L1 protein abundance is regulated by cyclin D-CDK4, and that inhibition of CDK4/6 in vivo elevates PD-L1 protein levels. Combining CDK4/6 inhibitor treatment with anti-PD-1 immunotherapy enhanced tumor regression and dramatically improved overall survival rates in mouse tumor models. Our study uncovered a novel molecular mechanism for regulating PD-L1 protein stability by a cell cycle kinase and revealed the potential for using combination treatment with CDK4/6 inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.012
       
  • 29INTrilaciclib (G1T28), a CDK4/6 inhibitor, enhances the efficacy of
           combination chemotherapy and immune checkpoint inhibitor treatment in
           preclinical models
    • Authors: Roberts P; Lai A, Sorrentino J, et al.
      Abstract: Background: While immune checkpoint inhibitors (ICI) are efficacious and lead to durable responses in patients with various cancers, only a minority of patients respond. An approach to increase the efficacy of ICI is to combine them with chemotherapy, in order to enhance immunogenic cell death and “prime” the immune system. However, chemotherapy itself can cause damage to various cell types of the immune system, potentially diminishing the activity of the ICI combination. Using trilaciclib, a short-acting IV CDK4/6 inhibitor that preserves hematopoietic stem cells and enhances immune system function during chemotherapy, we have developed a novel approach to preserve immune system function during chemotherapy to allow optimal activity of ICI.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.013
       
  • 2INInnovative drugs targeting IDO1 functions in neoplasia
    • Authors: Grohmann U; Macchiarulo A.
      Abstract: Background: Catabolism of amino acids is an ancient survival strategy that also controls immune responses in mammals. Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions, including neoplasia, in which it promotes immune unresponsiveness. However, IDO1 does not merely degrade tryptophan and produce immunoregulatory kynurenines but also acts as a signal-transducing molecule independently of its enzyme activity. IDO1’s signaling function relies on the presence of phosphorylable motifs in a region (small IDO1 domain) distant from the catalytic site (large IDO1 domain). Moreover, in the presence of the immunosuppressive cytokine TGF-β, the activation of the IDO1 signaling pathway has been shown to reprogram dendritic cells, the most professional antigen presenting cells, toward a stable and long term immunosuppressive phenotype that might possiby be relevant in the mechanisms of tumor immune escape. Although a potent and catalytic inhibitor of IDO1 is close to the market, being currently studied in a phase III trial in association with a checkpoint inhibitor, our data would suggest that in tumors dominated by high levels of TGF-β (such as colon cancers) IDO1 signaling rather than IDO1 catalytic activity coud be favoured. Therefore, drugs capable of inhibiting IDO1 signaling activity may be more effective in those contexts. Our hypothesis is that IDO1 exists in distinct conformations, associated with either catalytic or signaling activity, and that small compounds directly binding IDO1 may favor or unfavor the distinct conformations and thus IDO1's actions.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.001
       
  • 30INWhy is PI3K so hard'
    • Authors: Scaltriti M.
      Abstract: Hyperactivation of the PI3K-AKT-mTOR signaling cascade occurs in a plethora of cancer types. Both preclinical data and clinical studies suggest that this pathway is a valid pharmacological target in selected patient populations. However, intrinsic and acquired drug resistance, together with emergence of intolerable side effects, limits the use of PI3K inhibitors in the clinic. There are at least two reasons that potentially explain why PI3K is so hard to tackle pharmacologically. One is the triggering of adaptive responses following treatments with PI3K inhibitors that can circumvent the antitumor activity of these agents. Upon blockade of the PI3K-AKT axis, these compensatory pathways can still sustain cell viability and proliferation, bypassing the pharmacological pressure. Hypothesis-based combinatorial strategies may prevent these molecular feedbacks and increase the efficacy of PI3K inhibitors. Another intrinsic limitation of these drugs is their limited therapeutic window. Ways to overcome this problem are a better selection of patients who are more likely to respond to these inhibitors and a better way to deliver these compounds specifically to the tumor microenvironment.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.014
       
  • 31INAKT inhibitors and other new kids on the block
    • Authors: Siu L.
      Abstract: AKT mutations are uncommon in cancers with the AACR GENIE Project cohort of 27,290 patients demonstrating AKT1 alterations in 1.9%, AKT2 alterations in 1.6%, and AKT3 alterations in 1.3% of cases (Courtesy AACR GENIE). The development of first generation AKT inhibitors has been limited by poor therapeutic index and the unselected patient populations being treated with these compounds. AKT1 E17K is the predominant functionally activating mutation most frequently found in breast cancer, gynecological cancer, bladder, prostate and lung cancer. A recently published basket study of the pan-AKT kinase inhibitor AZD5363, demonstrated objective responses in tumors harboring this oncogenic mutation (Hyman et al. J Clin Oncol 2106). The first-in-human phase I study of ipatasertib (GDC-0068) was also reported in solid tumor patients with or without AKT pathway aberrations, and demonstrated stabilization in about 30% of patients whose disease were progressing on prior therapies (Saura et al. Cancer Dis 2017). Paired tumor biopsies demonstrated inhibition of multiple on-target effectors but upregulation of pERK and pHER3 were observed suggesting compensatory feedback following ipatasertib administration. The path forward for AKT inhibitors will involve selection of patients with molecular vulnerabilities for this target and also combination studies with inhibitors of other signaling pathways such as the RAS/MEK pathway. Catalytic mTOR inhibitors such as MLN0128 and AZD2014 are also undergoing clinical evaluation in multiple tumor types. Challenges associated with the development of these classes of compounds will be discussed.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.015
       
  • 32INCan adding PI3K inhibitors to the treatment cocktail alter
           outcome'
    • Authors: Lorusso P.
      Abstract: The PI3K/AKT/mTOR pathway (PI3K pathway) is an important cell signaling pathway in cancer, identified as important in cell growth regulation, proliferation and survival. Despite initial excitement over targeting this pathway, in the vast majority of solid tumors, even with mutational signatures involving PI3K pathway targets, PI3K “targeted treatment” of solid tumors has been disappointing. Investigators have been challenged with patient selection, and currently, except in select situations and with selective agents, multiple mechanisms have been identified lending support for a future of combination therapeutic strategies. Several preclinical scenarios have resulted in effective combinations, however, the clinical challenge lies in reproducing preclinical results, in part due to the complexity of human disease accounting for multiple mechanisms of resistance, but also in the clinical challenges of enhanced toxicity of combination therapy and the negative results obtained from the “one size fits all” combination treatment strategies. Defining a more personalized cancer approach with relevant agents that lack toxicity overlap is the ultimate goal to continued development of this class of agents.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.016
       
  • 33INInsights into the biology of class I PI3K isoforms and translation to
           the clinic
    • Authors: Vanhaesebroeck B.
      Abstract: Most solid tumours demonstrate genetic activation of the PI3K pathway. However, the clinical impact of PI3K-inhibitors, aimed at dampening cancer-cell-intrinsic PI3K activity, has been limited. Evidence now indicates that the clinical efficacy of PI3K-inhibition can also derive from: (1) interrupting the cancer cells’ responses to micro-environmental stimuli, illustrated by the approved PI3Kdelta-inhibitor idelalisib in B-cell malignancies, (2) stimulation of host anti-tumour immune-responses by inhibiting leukocyte-specific PI3Kisoforms such as PI3Kdelta (Nature 2014:510:407), a concept currently being tested in clinical trials. An overview of these efforts will be presented. A major outstanding question is the role of PI3Kalpha/PIK3CA in solid tumours. We recently discovered previously unappreciated cancer-relevant effects of physiological PIK3CA mutation (i.e. heterozygous, from the endogenous promotor), namely induction of centrosome amplification in cultured cells and mouse tissues, and increased in vitro cellular tolerance to whole genome doubling (Nat Commun 2017:8:1773). Such biological activities are linked to chromosomal instability and suggest that PI3K-activation may have the capacity to help shape the cancer genome. Recent studies have also indicated that PIK3CA mutations can be an early clonal event, occurring before whole genome doubling in some cancers. In cancers where PI3K pathway mutations are not clonal such as renal cell carcinoma, evidence indicates that the PI3K–AKT–mTOR pathway often becomes recurrently activated at multiple branch points during tumour-evolution. This occurs in separate subclones within the same tumour and is an example of so-called parallel evolution, converging upon PI3K activation. We will discuss the potential clinical exploitation of these findings in the use of PI3K inhibitors in cancer prevention and/or dampening tumour-evolution.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.017
       
  • 37INIs “hyper-progression” a relevant clinical item for patient with
           solid tumours candidate to check-point inhibitor treatment'
    • Authors: de Braud F; Di Nicola M, Damian S, et al.
      Abstract: Background: Immunotherapy with immune checkpoint inhibitors (ICIs) is modifying the standard of care for several solid tumours. Nevertheless, the results in terms of efficacy are still limited to a minority of patients even if the percentage of response differed among tumours type. The evaluation of response with ICI has been improved by the definition of new immune-related Response Criteria (irRC) that identified pseudo-progression followed by delayed tumour shrinkage in up to 10% of patients treated with anti CTLA-4 or anti PD1/PDL-1 agents. Afterward, hyper-progression (HP) after ICI administration has been recently reported but a mechanicistic explanation of the relationship with the ICI administration has not yet clearly identified. For this presentation, the obvious difficulty is to distinguish between resistance and consequent progression due to the tumour biology and a truly progression primed by ICI treatment.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.018
       
  • 38INKinesin spindle protein inhibitors as novel payload class for ADCs
    • Authors: Sommer A.
      Abstract: Background: The number of cytotoxic payload classes with different modes-of-action which have been successfully employed in antibody-drug conjugates (ADC) is still rather limited. So far, ADCs with microtubule inhibitors, DNA binding payloads, or topoisomerase I inhibitors have been advanced into clinical testing. To this end, the identification of ADC payload classes with a novel mode of action will increase therapeutic options. The kinesin spindle protein (KSP/Eg5/KIF11) is an ATP-dependent motor protein involved in the separation of centrosomes in G2/M phase which is an essential event in mitosis. KSP inhibitors (KSPi) have generated interest due to their high antitumor activity in preclinical models. However, transferring the preclinical potency of small molecule KSP inhibitors (SMOL KSPis) into highly efficient clinical regimens with a sufficient therapeutic window has remained challenging. Targeted delivery of payloads selectively to tumor cells while sparing normal cells may enlarge the therapeutic window of KSPis.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.019
       
  • 39INThe next generation of radioimmunotherapy: Targeted alpha therapy
           (TAT)
    • Authors: Molnar I; Burak E, Forbes J, et al.
      Abstract: Targeted alpha therapy (TAT) involves selective delivery of isotopes that emit highly energetic alpha particles to cancer cells leading to their ultimate destruction, while minimizing collateral damage to healthy surrounding cells. The high linear energy transfer of alpha particles makes it possible to consider targets with relatively low cellular expression levels (or concentration) and to treat hypoxic and chemotherapy resistant tumors. The limited emission of beta and gamma radiation from the appropriate alpha emitting isotopes significantly reduces the complexities of administration and decreases the chance of exposure to caregivers and family members. Despite the potential, clinical development of targeted alpha therapeutics has been slow due to a variety factors that will be discussed. Radium-223 dichloride, the only approved alpha therapy in clinical medicine, provides the proof of concept for internal alpha emitting radioisotope therapy in cancer treatment. 223RaCl2 is “targeted” via its fundamental physicochemical properties as it incorporates into the bone matrix at sites of bone formation. The interest in TAT is based partly on the clinical usefulness of 223RaCl2 in castration resistant prostate cancer. However, 223RaCl2 is only suitable for treating bone metastases, so new targeted therapies that aim to treat liquid and solid soft tissue tumors are now under clinical development. The clinical experience to date with TAT will be reviewed focusing on the status, advantages and disadvantages of different radioisotope payloads (213Bi, 225Ac, 211At, 212Pb and 227Th), targets (CD33, CD20, CD22, PSMA, HER2, somatostatin receptor and others), and targeting agents (small molecules, peptide and antibodies) that have been employed to date. The momentum in the TAT field is illustrated by a growing number of promising TAT compounds that are in or near starting clinical trials. The current status of these TAT molecules (225Ac-PSMA-617, 212Pb-AR-RMX, 225Ac-lintuzumab, FPX-01, 211At-BC8-B10, BAY1862864) will be discussed with particular attention to those agents that use 225Ac (t½ 10 days) and 227Th (t½ 18.7 days) as the therapeutic payload. The half-life of these two alpha emitting isotopes permits manufacturing and delivery of ready-to-use doses to patients. Biodistribution and dosimetry may require the use of a separate imaging radioimmunoconjugate when alpha isotopes with limited gamma emission are used. The potential role of TAT in hematological malignancies and in solid tumor treatment will also be discussed along with systemic and local administrations strategies, both of which may prove to have clinical utility in coming years.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.020
       
  • 40INA novel drug conjugate platform: Redefining the therapeutic window for
           ADCs
    • Authors: Babcook J; Davies R, Barnscher S, et al.
      Abstract: Background: Antibody drug conjugates (ADCs) can offer significant benefit to patients suffering from a variety of solid and liquid tumors by combining the specificity of monoclonal antibodies and the cellular cytotoxicity of antineoplastic small molecules. While ADCs have tremendous potential, dose-limiting toxicity remains the largest barrier to robust patient responses. Through the utilization of proprietary protease cleavable N-acyl sulfonamide (NAcS) linked hemiasterlin and auristatin payloads, we have generated highly efficacious ADCs with improved therapeutic indices. Antibody drug conjugates (ADCs) can offer significant benefit to patients suffering from a variety of solid and liquid tumors by combining the specificity of monoclonal antibodies and the cellular cytotoxicity of antineoplastic small molecules. While ADCs have tremendous potential, dose-limiting toxicity remains the largest barrier to robust patient responses. Through the utilization of proprietary protease cleavable N-acyl sulfonamide (NAcS) linked hemiasterlin and auristatin payloads, we have generated highly efficacious ADCs with improved therapeutic indices.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.021
       
  • 41OA phase I study of CPI-0610, a bromodomain and extra terminal protein
           (BET) inhibitor in patients with relapsed or refractory lymphoma
    • Authors: Blum K; Abramson J, Maris M, et al.
      Abstract: Background: NF-kB has been found to be constitutively activated in many lymphomas, such as diffuse large B-cell lymphomas (DLBCL), particularly the ABC subgroup. In preclinical studies, CPI-0610, a BET specific small molecule inhibitor, results in downregulation of NF-κB signaling activity, accompanied by loss of viability of ABC-DLBCL cell lines. Here we report the results from the first-in human Phase 1 study of CPI-0610 in patients with relapsed or refractory lymphomas (NCT01949883).
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy048
       
  • 42OA phase 1 study of CPI-1205, a small molecule inhibitor of EZH2,
           preliminary safety in patients with B-cell lymphomas
    • Authors: Harb W; Abramson J, Lunning M, et al.
      Abstract: Background: EZH2 is the catalytic subunit of the PRC2 complex, and plays an important role in transcriptional repression. EZH2 over-expression is correlated with poor prognosis. Hot spot mutations in EZH2 were first identified in GCB-DLBCL and follicular lymphoma (FL). CPI-1205 is a potent, selective, SAM-competitive EZH2 inhibitor. A Phase I study was conducted in B-cell lymphoma patients. Primary Objectives: Define maximum tolerated dose of CPI-1205 and the dose-limiting toxicities (DLTs).
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy048.001
       
  • 43OUnravelling the context specificity of signalling in KRAS mutant
           cancers: Implications for design of clinical trials
    • Authors: Banerji U; Stewart A, Coker E, et al.
      Abstract: Background: It has been shown that mutations alone are not the sole determinant of response to targeted agents, for example, BRAF mutations predict response to BRAF inhibitors in melanoma but not colon cancer due to differential EGFR signalling in colon cancer. We aimed to study any context-dependent differences in signalling pathways between pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) with KRAS mutations using a targeted phosphoproteomic approach in cell lines exposed to targeted anticancer drugs ex vivo.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy048.002
       
  • 44OCCTG IND.231: A phase 1 trial evaluating CX-5461 in patients with
           advanced solid tumors
    • Authors: Hilton J; Cescon D, Bedard P, et al.
      Abstract: Background: G-quadruplexes are secondary DNA structures that reversibly form in guanine-rich regions that can lead to replication fork collapse and double-stranded DNA breaks. Preclinical work by our group has demonstrated that CX-5461 can stabilize G-quadruplexes, resulting in synthetic lethality in BRCA1/2 deficient cell lines and xenograft models.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy048.003
       
  • 46OA Phase 1a/2a trial of AVID100, an anti-EGFR antibody-drug conjugate
    • Authors: Tolcher A; Papadopoulos K, Cole Y, et al.
      Abstract: Background: AVID100, an anti-EGFR-DM1 conjugate, showed potent activity in preclinical models in vitro and in vivo including in cell lines resistant to approved anti-EGFR mAbs.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy048.004
       
  • 47OPhase 1 study of bispecific HER2 antibody-drug conjugate MEDI4276 in
           patients with advanced HER2-positive breast or gastric cancer
    • Authors: Pegram M; Hamilton E, Tan A, et al.
      Abstract: Background: MEDI4276 is a HER2-bispecific antibody targeting two different epitopes on HER2, with site-specific conjugation via maleimidocaproyl linker to a potent tubulysin-based microtubule inhibitor. MEDI4276 demonstrates enhanced cellular internalization and cytolysis of HER2+ tumor cells in vitro, including T-DM1 resistant cells.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy048.005
       
  • 48OCC-122, a novel cereblon-modulating agent, in combination with
           obinutuzumab (GA101) in patients with relapsed and refractory (R/R) B-cell
           non-hodgkin lymphoma (NHL)
    • Authors: Michot J; Bouabdallah R, Doorduijn J, et al.
      Abstract: Background: Patients (pts) with NHL experiencing early relapse (ER) within two years of initial diagnosis and those double refractory (DR) to both rituximab and chemotherapy have particularly poor outcomes (Casulo et al JCO 2015; Gopal et al. NEJM 2014). Preliminary results from CC-122-NHL-001, the first study of CC-122, a novel cereblon-modulating agent, in combination with obinutuzumab (G), showed promising response rates in pts with R/R B-cell NHL (Michot et al Blood 2016). Herein, we report updated results for safety and efficacy from CC-122-NHL-001 (NCT02417285) with further 12 months follow up.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy048.006
       
  • 49ODownregulation of USP28 confers poorer overall survival to melanoma
           patients and causes resistance to RAF inhibitors
    • Authors: Saei A; Palafox M, Benoukraf T, et al.
      Abstract: Background: The mutation in BRAF kinase at V600 has been frequently reported in nearly 50% of melanoma patients resulting in the hyper-activation of MAPK pathway. As such, various inhibitors which target mutant BRAF have been developed including vemurafenib and dabrafenib both of which have demonstrated significant clinical outcomes. Nevertheless, both primary and acquired resistance reduce the overall response of patients to the therapy. So, the search of efficient biomarkers to stratify melanoma patients has become an imperative subject of research to enhance the efficacy of RAF inhibitor treatments and to decrease the rate of side effects due to the therapy. The mechanism of ubiquitination in controlling various functions such as stabilization of a protein cannot be neglected. A number of ubiquitin regulatory enzymes have been already shown to act on and regulate various component of MAPK pathway.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy048.007
       
  • 50OA first-in-human first-in-class (FIC) trial of the monocarboxylate
           transporter 1 (MCT1) inhibitor AZD3965 in patients with advanced solid
           tumours
    • Authors: Plummer R; Halford S, Jones P, et al.
      Abstract: Background: A key metabolic alteration in tumour cells is increased dependency on glycolysis, resulting in the production of lactate which is transported out of cells by MCTs. Inhibition of MCT-1 can constrain cancer cell growth in preclinical models. We report results on the phase I study of AZD3965, a FIC inhibitor of MCT-1.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy048.008
       
  • 51PActive immunotherapy with a VEGF targeted vaccine HeberSaVax: The road
           so far and the future ahead
    • Authors: Bequet-Romero M; Díaz Y, Ramírez J, et al.
      Abstract: Background: The vascular endothelial growth factor (VEGF) plays a central role in angiogenesis and immunosuppressive cascades inherent to tumor development. Success of drugs targeting this growth factor and their receptors signaling cascade built upon these facts. Such passive targeting of VEGF/VEGFR pathway had two major caveats: non-manageable side effects and the induction of resistance phenomena. To overcome some of these problems we design an active immunization approach based on the use of a functionally deficient VEGF 121 isoform as antigen. Herein we present preclinical and clinical development data of HeberSaVax vaccine (formerly known as CIGB-247).
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047
       
  • 52PA novel rMVA combination immunotherapy triggers potent innate and
           adaptive immune responses against established tumors
    • Authors: Medina J; Hinterberger M, Testori M, et al.
      Abstract: Background: Virus-based vaccines and appropriate costimulation enhance potent antigen-specific T cell immunity against cancer. In the present study we exploit both innate and adaptive immune responses triggered by a novel recombinant modified vaccinia virus Ankara (rMVA) encoding costimulatory CD40L against solid tumors in combination regimes to overcome tumor-induced resistance to immunotherapy.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.001
       
  • 53PImpact of chronic hepatitis virus infection on the feasibility and
           efficacy for Asian patients with hepatocellular carcinoma in phase I
           clinical trials
    • Authors: Koyama T; Kondo S, Shimizu T, et al.
      Abstract: Background: In Asia, chronic hepatitis B and C virus infections (CHVI) are major risk factors for liver fibrosis and hepatocellular carcinoma (HCC). Patients with advanced HCC have limited effective therapeutic options and are potential candidates for early phase clinical trials for new anti-cancer agents. The impact of CHVI on the feasibility and efficacy for patients with HCC in Phase I trials (P-Is) has not been reported or elucidated in Western countries.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.002
       
  • 54PIdentifying the oncogenic role of USP10 as the regulator of PTEN
           function in breast cancer
    • Authors: Kumari N; Saei A, Lalith C, et al.
      Abstract: Background: The PI3K pathway is the most commonly activated signaling pathway in human cancer. The loss of PTEN further contributes to the tumorigenic impact of the active PI3K pathway, and have direct effect on prognosis of breast cancer. Although many small molecules are used in clinic to target the PI3K pathway, only minority of breast cancer patients respond to these drugs. This study identified the role of a deubiquitinating enzyme, USP10 in the regulation of PI3K pathway in breast cancer.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.003
       
  • 55PProtein expression and clinical significance of the NEDDylation pathway
           in myelodysplastic syndrome
    • Authors: Majidi F; Strapatsas J, Brille S, et al.
      Abstract: Background: A phase I clinical trial of Pevonedistat (MLN4924), a NEDD8-activating enzyme inhibitor, in AML and MDS showed modest clinical activity as a single agent. A phase II trial with Pevonedistat plus Azacytidine versus single-agent Aza is ongoing. As yet, there is no data regarding activity or dysfunction of the NEDDylation pathway in MDS. We examined NEDDylation pathway protein expression and its prognostic relevance in MDS.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.004
       
  • 56PClinicopathological, predictive and prognostic significance of
           XRCC1-Ligase III heterodimer expression in ovarian cancer
    • Authors: Alabdullah M; Moseley P, Chan S, et al.
      Abstract: Background: Ovarian cancer is the leading cause of death from gynaecologic malignancy. The platinum-based chemotherapy remains the standard initial treatment for ovarian cancer patients. Platinum resistance and recurrence is a formidable problem that impacts clinical outcomes in ovarian cancer patients. XRCC1-Ligase III heterodimer is a key player in DNA base excision repair (BER), single strand break repair (SSBR) and alternative non-homologous end joining (alt-NHEJ) pathway for double strand breaks (DSBs) Our objective was to evaluate if XRCC1-ligase III expressions could predict platinum and clinical outcome in epithelial ovarian cancers.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.005
       
  • 57PNOX66 plus low dose carboplatin: A phase 1 safety and signalling study
    • Authors: Kelly G; Messina M, Minns I.
      Abstract: Background: NOX66 is under development to enhance standard chemotherapy and radiotherapy. The target of idronoxil (the active constituent of NOX66), ENOX2, is an optimal candidate anti-cancer drug due to its tumour-cell specific expression. Inhibition of ENOX2 leads to a disruption of the TMEP, causing a cascade of intracellular actions leading to direct cytotoxicity and inhibition of DNA repair pathways. Three Phase 1 studies are underway to observe safety and efficacy signals - investigating multiple dose levels of NOX66 as monotherapy and in combination with carboplatin, palliative dose EBRT, and 177Lu-PSMA (a theranostic for treatment of prostate cancer). Data has previously been presented showing NOX66 400mg to be well tolerated as monotherapy and in combination with carboplatin. Here we present data for patients receiving 800mg NOX66.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.006
       
  • 58PPharmacokinetics of ZR2002, a combi-molecule with EGFR and DNA-damaging
           properties and its efficacy in an orthotopic glioblastoma mouse model
    • Authors: Sharifi Z; Meehan B, Daniel P, et al.
      Abstract: Background: Glioblastoma multiforme (GBM) is the most aggressive form of malignant primary brain tumors in adults with a survival of only 12-15 months. We previously showed that ZR2002, a chimeric aminoquinazoline designed to possess mixed EGFR tyrosine kinase (TK) inhibitory and DNA targeting properties exhibits potent activity against GBM established cell lines and brain tumor stem cells in vitro.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.007
       
  • 59PSynergistic effects of PARP inhibitors and ionizing radiation on growth
           and survival of rhabdomyosarcoma cells
    • Authors: Megiorni F; Camero S, Ceccarelli S, et al.
      Abstract: Background: The poly(ADP-ribose) polymerase inhibitors (PARPi) are used in a wide range of human solid tumours but a limited evidence is reported in rhabdomyosarcoma (RMS), the most frequent soft-tissue sarcoma in children and adolescents. Our study evaluated the effects of Olaparib, a specific PARP1/2 inhibitor, and AZD2461, a newly synthetized PARP1/2/3 inhibitor, in RMS cells both as single-agent and in combination with ionizing radiation (IR).
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.008
       
  • 60PInvestigating the role of nuclear sphingosine kinase 1 (SphK1) in lung
           cancer
    • Authors: Napolitano F; Rosa R, D'Amato V, et al.
      Abstract: Background: Sphingosine kinases (SphKs) are enzymes catalyzing the formation of a bioactive lipid messenger, sphingosine-1-phosphate (S1P) through phosphorylation of sphingosine. So far, two isoforms of SphK have been described: SphK1, which has cytosolic distribution, and SphK2, known to locate predominantly in the nucleus. Overactivation of SphKs is involved in tumor growth and progression through regulation of cell proliferation and apoptosis.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.009
       
  • 61PPreclinical evaluation of BET-bromodomain inhibitor TEN-010 as
           monotherapy and combination therapy in MYC-driven neuroblastoma
    • Authors: Firle K; Szymansky A, Witthauer M, et al.
      Abstract: Background: Despite intensive multimodal therapy, more than 50% of children with high-risk neuroblastoma eventually succumb to the disease. MYC signaling is a predominant driver of high-risk neuroblastoma, caused either by amplification of MYCN or by activation of cMYC. The bromodomain and extra-terminal (BET) domain-containing protein BRD4 was reported to cooperate with MYCN in the epigenetic regulation of super-enhancer driven genes in neuroblastoma. The BET inhibitors JQ1 and OTX015 were shown to repress BET/MYCN-mediated transcriptional control and antitumoral efficacy in MYCN-driven neuroblastoma. The potent BET inhibitor TEN-010, a derivative of JQ1, is currently in clinical trials for various MYC-driven adult tumors. Its efficacy against neuroblastoma is yet to be established.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.010
       
  • 62PTargeting Wnt pathway reduces primary tumor and metastasis in breast
           cancer models
    • Authors: Goswami S.
      Abstract: Background: Biomarkers CD44 and CD24 are routinely used to identify breast cancer stem cells (BCSCs). BCSCs are chemotherapy resistant and bear high tumorigenesis and metastatic capabilities. Wnt/β-catenin signaling is involved in maintaining CSCs and thus is responsible for recurrence and poor prognosis. Role of Wnt receptor LRP6 in breast cancer promotion and progression is well known. We hypothesized that interactions between cancer cells, macrophages, and endothelial cells induce cancer stemness via activation of Wnt/-β catenin pathway, and blocking that pathway will reduce primary and metastatic tumors.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.011
       
  • 63PEXPRESS study: A multicenter, prospective trial in progress exploring
           the association between low level of genomic alteration and exceptional
           and unexpected response to targeted therapies in patients with solid
           tumors
    • Authors: Le Saux O; Italiano A, Spaeth D, et al.
      Abstract: Background: Most targeted therapies in cancer have reached approval based on clinical studies performed in unselected patients. Small subsets of patients present exceptional responses (ER), which could be driven by a low level of genomic alterations in genes identified as causally implicated in cancer.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.012
       
  • 64PmiRNA 200c sensitize pancreatic cancer stem cells to carbon ion beam
           irradiation
    • Authors: Sai S; Suzuki M, Kim E.
      Abstract: Background: Increasing evidence shows that microRNAs (miRNA), a family of small non-coding RNAs, play a pivotal role in regulating mRNA translation. Recently, some miRNAs have been shown to be involved in regulating cancer stem cell (CSC) properties. Because CSCs are highly resistant to conventional chemotherapy and radiation therapy, and heavy ion radiotherapy is effective in treating those of chemo-radioresistant cancers, in this study we attempt to explore new molecular mechanisms of CSC targeted therapies by carbon ion beam alone or in combination with a miRNA200c mimic.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.013
       
  • 65PEpigenetic regulation of tumor metabolism
    • Authors: Shivanna S; Liu J, Pawling J, et al.
      Abstract: Background: Cancer cells rewire metabolic pathways to enable their uncontrolled proliferation through a phenomenon called the Warburg effect. Cancer cells adopt this metabolic diversion through epigenetic modifications such as chromatin remodeling and histone acetylation (H3k27ac). Such inheritable modifications influence DNA accessibility to regulate gene expression. One such epigenetic modifier, WD40 protein, is shown to be involved in regulation of transcription, and protein modifications. Its dysfunction might influence the development of diseases such as cancer and metabolic diseases. Our lab has discovered a WD40 containing protein which we refer to as WD40 that serves as an oncogenic driver in breast cancer cells. Based on preliminary findings, we propose that WD40 functions as an oncogenic driver, which plays a critical role in epigenetic reprogramming in genes that drive the Warburg effect and that promote the enrichment of CD44high/CD24low population.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.014
       
  • 66PPharmacological activity of CB-103: An oral pan-NOTCH inhibitor
           targeting the NOTCH transcription complex
    • Authors: Weber D; Lehal R, Frismantas V, et al.
      Abstract: Background: NOTCH signalling is a key development pathway whose aberrant activation is known to play a role in multiple human cancers. When the NOTCH pathway is activated by genetic lesions (over expression of ligands/receptors, GOF mutations in receptors, chromosomal translocations), it becomes a major oncogenic driver for NOTCH-dependent cancers and resistance to standard of care treatment.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.015
       
  • 67PDNA promoter methylation status and protein expression of SHh and IHh
           in serous ovarian carcinomas
    • Authors: Karin V; Skrtic A, Skenderi F, et al.
      Abstract: Background: The Hedgehog (Hh) signaling pathway is an evolutionarily conserved pathway of signal transmission which plays a significant role in the normal embryonic development of invertebrates and vertebrates. In the adult organism, Hh signaling pathway is mostly inactive or poorly active while its hyperactivation is associated with carcinogenesis. Binding of the Hh ligands, Sonic Hedgehog (SHh), Indian Hedgehog (IHh) and Desert Hedgehog (DHh) along with PTCH protein activates Hh signaling resulting in increased activity of the GLI transcription factors that activate targeted genes. The status of Hh pathway components in serous ovarian carcinomas is poorly understood.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.016
       
  • 68PMicroRNA-21 functions as a prognosis predictor in head of pancreas
           tumor
    • Authors: Aksoy F; Aksoy S, Tunca B, et al.
      Abstract: Background: Pancreatic ductal adenocarnoma (PDAC) is the fourth leading cause of cancer related death in men and women.15 Approximately 60-70% of PDACs arise in the head of the pancreas. Since the early diagnosis of head of the pancreas tumors is difficult, patients are frequently at an advanced stage at the time of diagnosis and have extremely short survival. Furthermore, the mechanism of pathogenesis in PDAC is not completely understood and there are currently no effective therapies. Recent studies demonstrated that miRNAs play critical roles in various types of tumors including PDAC and thereby has high diagnostic value for screening and great clinical value for cancer therapy. The aim of the present study was to determine the expression profile of miRNAs in head of pancreas and examine its association with prognosis.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.017
       
  • 69PRAB25 a potential therapeutic target in luminal B breast cancer
           molecular subtype
    • Authors: Addou-Klouche L.
      Abstract: Background: Breast cancer is a complex and heterogeneous disease. Luminal B breast cancers molecular subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. Although they express hormone receptors, their metastatic risk and resistance to hormone therapy and to conventional chemotherapy demand to develop appropriate therapies. Studies have suggested that RAB 25 (Ras-related protein 25) a member of Rab small GTPase family, is involved in Luminal B breast cancer pathogenesis. To better understand this subtype we compared RAB25 DNA copy number aberrations (CNAs) and expression level in luminal B tumors with those observed in breast cancers of the other molecular subtypes.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.018
       
  • 70PmTORC1 and its downstream effectors predict poor outcome in primary
           epithelial ovarian cancer
    • Authors: Alabdullah M; Miligy I, Moseley P, et al.
      Abstract: Background: Ovarian cancer is associated with the highest mortality rate among gynaecologic malignancies. There is a need to refine classification of ovarian cancer and identify novel targets. The mammalian target of rapamycin (mTOR) pathway has a crucial role in the regulation of translation of specific proteins associated with ovarian cancer progression. The major downstream effectors of mTOR are eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and ribosomal protein S6 kinase (p70S6K). We aimed to investigate the biological significance of this pathway in ovarian cancer.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.019
       
  • 71PThe effect of hTERT repression on the TERRA expression and telomere
           length in gastric cancer
    • Authors: Akhavan H; Vahidi S, Sorayyayi S, et al.
      Abstract: Background: Telomeres play a vital role in maintaining the integrity of the genome. Mammalian telomeres are certainly transcribed into telomeric repeat-containing RNA (TERRA). This Long non-coding RNA participates in the regulation of telomere length and telomerase activity. As reported, lncRNAs play important roles in gastric cancer progression. Telomerase and its major catalytic subunit (hTERT) are upregulated in most cancers, including gastric cancer. RNA interference (RNAi) has been proven to be a powerful tool for gene knockdown and hold good promise for the treatment of human diseases including cancer. In this study, we investigated the effect of hTERT repression on the TERRA expression and telomere length in multiple passages.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.020
       
  • 72PUp-regulation of miR-1266-5p suppressed hTERT expression and telomerase
           activity in cancer cell lines
    • Authors: Hosseini-Asl S; Sorayyayi S, Vahidi S.
      Abstract: Background: Telomerase is in charge of telomere extending and is triggered in around 90% of cancers. hTERT is the controlling subunit of telomerase and plays a critical role in the activation of telomerase. The mechanism through which hTERT regulate the invasion and metastasis of cancer is unclear. miRNAs can regulate the expression of hTERT. It was previously reported that miR-1266 can target hTERT in gastric cancer. In this study, we have made the first report of miR-1266-5p role on the hTERT expression, telomerase activity, and biological functions, including cell proliferation and cell cycle in AGS, MCF7, A375, and HepG2 cell lines.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.021
       
  • 73PRegulation of hnRNPA1 by microRNAs controls the miR-18a–K-RAS axis in
           chemotherapy-resistant ovarian cancer
    • Authors: Rodriguez-Aguayo C; Bayraktar E, Ivan C, et al.
      Abstract: Background: The regulation of microRNA (miRNA) biogenesis, function and degradation is regulated by a range of mechanisms involving RNA-binding-proteins and protein-RNA interactions. The potential contribution of regulatory miRNAs to the expression of these RNA interactor proteins that could control other miRNAs expression is still unclear.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.022
       
  • 74PPromoter hypermethylation of Wnt pathway inhibitor SFRP1 gene and its
           expression levels in human astrocytomas
    • Authors: Kafka A; Karin V, Serman L, et al.
      Abstract: Background: Astrocytomas are the most common primary brain tumors that are on the basis of their histology, molecular characteristics and prognosis classified into 4 different malignancy grades. As one of the key oncogenic pathways in human malignancies that has been associated to many human cancers the Wnt signaling pathway has also been implicated in gliomagenesis. In the present study we aimed to identify the status of SFRP1 promoter hypermethylation in different malignancy grades of astrocytoma and assess its parallel expression levels in search for their connection with clinical data.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.023
       
  • 75PRole of p21-activated kinase (PAK) in K-RAS mutant human colorectal
           cancer models
    • Authors: Orsini R; D'Amato V, Rosa R, et al.
      Abstract: Background: RAS mutations promote resistance to anti-EGFR targeted agents in colorectal cancers (CRCs) by disabling RAS intrinsic GTPase activity, therefore increasing an EGFR-independent activation of PI3K/AKT and MAPK pathways. However, up to 25% of CRC patients are refractory to EGFR inhibitors even in absence of the above- mentioned mutations. It is, then, crucial to identify alternate routes of kinase pathway activation that sustain the constitutive or acquired resistant phenotype. p21-Activated Kinase (PAK) family proteins play an important role in the context of cancer progression, and are related to Ras pathway. Therefore, we focused on the involvement of PAK signaling pathway in the onset of cetuximab resistance.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.024
       
  • 76PRe-sensitising endocrine resistant ER+ breast cancer by targeting
           epigenetic modifying enzymes
    • Authors: Borchert G; Casciello F, Kelly G, et al.
      Abstract: Background: Estrogen drives cellular proliferation and survival in estrogen receptor-positive (ER+) breast cancer. Exposure to endogenous or exogenous estrogen is a well-established cause of breast cancer and target of endocrine therapies such as antiestrogens and aromatase inhibitors. However, their efficacy is limited by intrinsic or acquired endocrine resistance which remains a significant clinical challenge. A third of patients given the antiestrogen therapy tamoxifen for 5 years develop recurrence and metastasis within 15 years. Gene expression studies of endocrine resistance suggest the dysregulation of epigenetic enzymes has an important role in survival signaling and cellular proliferation in acquired endocrine resistance. The development of epigenetic modifier inhibitors offers the promise of dynamically targeting mediators of acquired resistance that may be exploited as biomarkers and therapeutic targets to improve patient prognosis.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.025
       
  • 77PLeptin receptor gene (A/G) polymorphism (rs1137101) and renal cell
           carcinoma
    • Authors: Alhanafy A; Zahran A, Abdalla A, et al.
      Abstract: Background: Obesity and High body mass index are associated with a higher risk of developing renal cell carcinoma (RCC). Leptin is a peptide hormone produced predominantly by adipocytes that is elevated in obese individuals. The main function of leptin is to regulate body weight and appetite. Leptin may play a role in carcinogenesis of many cancers including RCC. We aimed to investigate the role of leptin Receptor gene (A/G) polymorphism (rs1137101) in RCC.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.026
       
  • 79PRole of DNA methylation in early detection of gastric cancer in patient
           with chronic atrophied gastritis
    • Authors: Djuraev F.
      Abstract: Background: Chronic atrophied gastritis is the most important and independent risk factor for gastric adenocarcinoma, i.e., precancerous condition, especially in cases of intestinal metaplasia development.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.028
       
  • 7INTargeting histone H3K36me3-deficient cancers
    • Authors: Humphrey T.
      Abstract: SETD2-dependent histone H3 lysine 36 trimethylation (H3K36me3) plays a central role in both maintaining genome stability and in suppressing tumorigenesis, and is frequently depleted in particular cancer types. We find this histone mark plays an important role in promoting homologous recombination (HR) repair of DNA double-strand breaks. Further, H3K36me3 also performs an essential role in facilitating DNA replication following WEE1 kinase inhibition, through promoting efficient deoxyribonucleotide synthesis. Accordingly, H3K36me3-deficient cancers can be specifically targeted using the WEE1 inhibitor, AZD1775, resulting in replicative catastrophe and cell death. The use of AZD1775 to target H3K36me3-deficient cancers is now in clinical trials. Mechanistic insights into the targeting of H3K36me3-deficient cancers with AZD1775 and its implications will be presented.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.002
       
  • 80PDevelopment of novel modified aptamers to target Axl receptor in
           ovarian cancer
    • Authors: Amero P; Rodriguez-Aguayo C, Lokesh G, et al.
      Abstract: Background: Ovarian cancer is the fifth leading cause of cancer death in women and the most lethal gynecologic malignancy with a rate of survival of 40%. Aberrant GAS6-AXL signaling pathways are associated with many human diseases, including bone diseases, immune-suppression, fibrosis, cancer progression and metastasis. Experimental evidences demonstrated that patients expressing high levels of Axl shows shorter over-survival than patients expressing low levels of Axl in epithelial ovarian cancer. Therefore, there is the need to find novel strategies for silencing and blocking this signaling pathway and the dissemination of ovarian cancer.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.029
       
  • 81PSimultaneous use of erythropoietin and LFM-A13 as a new therapeutic
           approach for colorectal cancer
    • Authors: Hermanowicz J; Tankiewicz-Kwedlo A, Surażyński A, et al.
      Abstract: Background: Btk is non-receptor tyrosine kinases involved in the activation of signaling pathways responsible for maturation and viability of the cells. It plays an important role in the development of B-cell tumors, activating antiapoptotic pathways. Btk has previously been reported to be overexpressed in prostate cancer which correlated with cancer grades. Colorectal cancer is among the five most frequent causes for cancer-related deaths in Europe. This kind of cancer often accompanied by anemia which is treated with erythropoietin supplement. The aim of this study was to assess the effects of combination therapy with erythropoiethin beta (Epo) and LFM-A13 (Btk inhibitor) on colorectal carcinoma cells both in in vitro and in animal models.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.030
       
  • 82PIntroduction of a novel cancer cell targeted fusion protein: DT386-BR2
    • Authors: Jahanian-Najafabadi A; Shafiee F, Rabbani M.
      Abstract: Background: Due to the adverse side effects of current cancer chemotherapeutics development of targeted anti-cancer medications is under intensive focus. In the present study a fusion protein consisting of the catalytic and translocation domains of diphtheria toxin fused to BR2, a cancer specific cell penetrating peptide, was produced as a new targeted anti-cancer agent and its cytotoxic effects on various cell lines including MCF-7 and HeLa (as cancerous), and HEK293 and HUVEC (as normal) cell lines was evaluated.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.031
       
  • 83PArtemisia absinthium extract loaded polymeric nanoparticles as the
           therapeutic remedy for breast cancer
    • Authors: Mughees M; Samim M, Wajid S.
      Abstract: Background: Besides significant progress in the field of cancer therapy, breast cancer remains the major ongoing health problem among the women worldwide because of the side effects of available drugs. This problem can be overcome by loading herbal extract into the polymeric nanoparticles that will aid in site-specific drug delivery and increase in the retention time of drug, thereby improving therapeutic efficacy.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.032
       
  • 84PDual inhibition of AXL and FN14 sensitizes cisplatin in resistant
           non-small cell lung carcinoma by inducing higher caspase 3 cleavage
           through FHIT upregulation, both in vivo and in vitro
    • Authors: Mukherjee S; Suresh D, Zambre A, et al.
      Abstract: Background: NSCLC patients undergoing platin chemotherapy often develop resistance within 9-12 months and drug-resistance is the primary reason for the low median survival of 10-14 months among stage IV patients. Therefore, resistance is the fundamental therapeutic limitation in the later part of the progressive disease. Researchers showed that suppressed Caspase-3 is one of the primary reasons for failure to induce apoptosis by the cell during cisplatin resistance. Recently, AXL and TWEAK/FN14 pathways have been shown to be upregulated in cisplatin-resistant cells causing activation of EMT and survival pathways. Therefore, we examined whether targeted dual inhibition of AXL and FN14 successfully reverses the cisplatin resistance in NSCLC.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.033
       
  • 85PRepurposing chemotherapy drugs: The induction of immunogenic cell death
           in tumor cells as a tool leading to new formulations of cancer vaccines
    • Authors: Infante-Crúz A; Bernal-Estévez D, Parra-López C.
      Abstract: Background: Certain chemotherapy and radiotherapy regimens induce Immunogenic Cell Death (ICD) in tumor cells, contributing to the control of tumors by T cells. Markers of ICD includes HMGB-1 and ATP, expression of phosphatidylserine and Calreticulin (CRT) on the surface of apoptotic cells. ICD promotes the maturation of dendritic cells (DC) and the further activation of CTLs. This work was oriented to the implementation of an in vitro screening system of tumor cells, to induce ICD for their possible use in the immunotherapy of cancer in the future.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.034
       
  • 86PPim1 promotes ovarian cancer growth and the Warburg effect via
           c-Myc-glycolysis signaling axis
    • Authors: Wu Y; Deng Y, Duan Y, et al.
      Abstract: Background: Ovarian cancer (OC) is the second most common gynecologic malignancy, but its mortality ranks the highest in the world. Pim1, belongs to a group of constitutively activated serine/threonine kinases, has been reported in many types of cancer. Little is known about Pim1 in OC.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.035
       
  • 87PTowards the identification of the mechanism of action of antitumor
           1-methyl-D-tryptophan
    • Authors: Pallotta M; Iacono A, Albini E, et al.
      Abstract: Background: In recent years, tryptophan degradation has received increasing attention as a potent immunosuppressive mechanism involved in the maintenance of immunological tolerance in both tumor draining lymph nodes and tumors. Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan metabolizing enzyme and its mechanisms of action as an immune regulator involves tryptophan deprivation, production of immunosuppressive metabolites (kynurenines), and activation of signaling events through binding of tyrosine phosphatases (SHPs). IDO1 is chronically activated in many cancer patients and its expression and enzyme activity correlate with a poor prognosis in patients with various cancers. In the past, IDO1 inhibition was mostly achieved using the racemic mixture of 1-D,L-methyltryptophan (1-MT). As it became apparent that IDO1 inhibition may be a promising target for cancer therapy, the individual stereoisomers of 1-MT were investigated in more details. 1-L-MT was shown to more effectively inhibit IDO1 in enzyme assays and in cancer cell lines. However, 1-D-MT showed superior anti-tumor activity in mouse models and was therefore chosen for clinical trials. 1-D-MT is currently being tested in phase II clinical trials (indoximod) as an adjunct to conventional chemotherapy, although its immunostimulatory mechanism is still unknown. We here investigated whether 1-D-MT could interfere with IDO1 signaling rather than catalytic activity.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.036
       
  • 88PRelationship between functions and intracellular localization of the
           immune checkpoint target indoleamine 2,3-dioxygenase 1
    • Authors: Iacono A; Pompa A, De Marchis F, et al.
      Abstract: Background: Indoleamine 2,3-dioxygenase (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions. In cancer, IDO1 can either be expressed directly by the tumor cells themselves, or induced indirectly in host antigen presenting cells by the tumor and its expression has been associated with a worse clinical outcome in a variety of cancers, such as melanoma, ovarian cancer, and colorectal cancer. This consideration has driven to the definition of IDO1 as an investigational immune checkpoint target and to the development of several IDO1 inhibitors, some of which have entered clinical evaluation. Its mechanisms of action as an immune regulator, is composite and involves tryptophan deprivation and production of immunosuppressive metabolites (kynurenines). We recently demonstrated that IDO1 also acts as a signal-transducing molecule, independently of its enzymic function. In particular, in a microenvironment dominated by TGF-β, we found that IDO1 is involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in plasmacytoid dendritic cells (pDCs), a DC subset. In the literature, IDO1 has been described as a protein with a cytoplasmic localization. However, no thorough analysis of modifications of this localization in different conditions has been performed so far.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.037
       
  • 89PA polyphenol-rich extract from olive-mill waste waters targets the
           IL-6/STAT3 pathway in prostate cancer cell lines
    • Authors: Albini A; Baci D, Bruno A, et al.
      Abstract: Background: Cancer chemoprevention by dietary phytochemicals is particularly attractive for their potential low toxicity and for their ability to modulate a plethora of signal transduction pathways in biological processes associated with cancer. Olive oil, a major component of the Mediterranean diet, is an abundant source of phenolic compounds. Olive oil production is associated with the generation of waste material, termed ‘olive mill wastewaters’ (OMWW), that have been reported to be enriched in polyphenols. Here we investigated whether the use of purified extracts from OMWW (A009) might be effective in exerting chemopreventive activities in three different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCap) in vitro.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.038
       
  • 90PCytotoxicity of methanol extracts of 10 Cameroonian medicinal plants
           towards multi-factorial drug-resistant cancer cell lines
    • Authors: Flora M.
      Abstract: Background: Cancer chemotherapy is still hampered by clinical failures due to multi-drug resistance (MDR) of tumor cells. In the present study, we have investigated the cytotoxicity of 20 methanol extracts from 10 medicinal plants against the sensitive leukemia CCRF-CEM cells. The most cytotoxic extracts were then further tested on a panel of 8 human cancer cell lines, including various MDR phenotypes.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.039
       
  • 91PNovel effect of acetyl-11-keto-boswellic acid (AKBA) on
           mitophagy-induced apoptosis using cellular proteomic profiling
    • Authors: Al Zadjali F.
      Abstract: Background: Terpenoids and their potential analogues have attracted recent attention to their anti-cancer activity with lower adverse effects. Acetyl-11-keto-boswellic acid (AKBA) is a derivative of boswellic acid that exerts anti-cancer properties against different types of cancer cells. AKBA is known to induce apoptosis via activation of caspase 8 and also induction of epigenetic pathways via regulation of histone deacetylase gene expression. However, molecular targets and pathways are not identified. In this study we implemented in-depth non-labelled proteomic profiling of MCF-7 breast cancer cells treated with AKBA.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.040
       
  • 93PIn silico identification and in vitro assessment of a potential
           anticancer peptide sequence retrieved from the Red sea metagenomics
           library
    • Authors: Imam M; Amleh A.
      Abstract: Background: Cancer burden as a worldwide health issue arises from its increasing incidence together with depletion of efficacious treatment modalities. The current available treatments for cancer are surgery, radiotherapy and chemotherapy. The pharmaceutical industry is adopting a new paradigm shift towards a newer class of peptide-based drug that is expected to overcome the drawbacks of the conventional cancer therapeutics by offering more selectivity, easier synthesis, a wider safety profile and a lower cost of manufacture. The interest in peptides as anticancer agents began in the last few decades owing to their intrinsic properties, such as cationicity and small size, enabling them to compete as an efficacious anticancer agent.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.041
       
  • 94PNew insights in the antitumor effects of β-caryophyllene in breast
           cancer cells: The role of cannabinoid and adrenergic systems
    • Authors: Di Sotto A; Romaniello D, Freddoni G, et al.
      Abstract: Background: Triple-negative breast cancer (TNBC) is an aggressive disease, with poor therapeutic alternatives, whose incidence and mortality seem to be increased by smoking habit. In line with our previous evidence (Di Giacomo et al. Food Chem Toxicol 2018,111:393), we evaluated the antitumor properties of the natural sesquiterpene β-caryophyllene (CRY) in triple negative breast cancer as a possible novel targeted therapeutic strategy. Particularly, its effect on the molecular pathways of STAT3 and IL-8, and the involvement of cannabinoid and β2-adrenergic systems, whose control on cell proliferation has been reported, were studied.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.042
       
  • 95PEnergy restriction as a novel approach targeting breast cancer stem
           cells multi-drug resistance
    • Authors: Zaher D; Omar H.
      Abstract: Background: Breast cancer (BC) is the most commonly diagnosed cancer in women worldwide. The progression, metastasis and drug resistance of breast cancer cells were suggested to be driven by a special population within the tumor called cancer stem cells (CSC). Targeting CSC is extremely challenging due to the high expression levels of ATP-binding cassette (ABC) transporters which facilitates the multi drug resistance (MDR) capacity of CSC. The aim of this work was to test whether Energy restriction mimetic agents (ERMAs) as OSU-CG5 can counteract cancer multidrug resistance by limiting the availability of energy in CSC. In addition to exploit the mechanistic synergy between OSU-CG5 and a conventional chemotherapeutic agent as Doxorubicin.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.043
       
  • 96PDelivery of paclitaxel and everolimus in dual-targeted polymeric
           nanoparticles to breast cancer cells
    • Authors: Houdaihed L; Evans J, Allen C.
      Abstract: Background: Paclitaxel (PTX) is an essential component of the first-line treatment in breast cancer (BC). However, the conventional PTX formulation currently used has been associated with many dose-limiting toxicities. mTOR inhibitors, such as everolimus (EVER), were found to increase sensitivity to PTX in BC. Importantly, administering PTX and EVER at a synergistic ratio could allow for reducing the dose and toxicities of PTX. BC tumors co-expressing HER2 and EGFR were shown to have poor prognosis and reduced survival compared to other BC subtypes. Therefore, this research aims to develop a dual-targeted polymeric nanoparticle (NP) formulation encapsulating PTX and EVER at the synergistic molar ratio to improve cytotoxicity and cellular uptake in BC cells co-expressing HER2 and EGFR.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.044
       
  • 97PVascular targeted photodynamic therapy for pancreatic ductal
           adenocarcinoma: A pre-clinical success
    • Authors: Goldschmidt R; Koudinova N, Sasson K, et al.
      Abstract: Background: Vascular targeted photodynamic therapy (VTP) is based on in-situ photosensitization of a circulating drug leading to intravascular reactive oxygen species (ROS) generation and the subsequent tumors’ blood vessel occlusion that lead to the tumor necrosis. We have developed a series of bacteriochlorophyll derivatives, among them WST11 (TOOKAD®-Soluble) a water-soluble agent that has just been granted approval by the European community (EMA) for the treatment of early/intermediate prostate cancer. Application to other cancers, specifically to pancreatic ductal adenocarcinoma (PDAC) is being evaluated and may require adjustments of the treatment conditions. The following work presents the first pre-clinical results using WST11-VTP to treat syngeneic PDAC in mice.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.045
       
  • 98PEffect of prolactin receptor antagonist in different cancer models
    • Authors: Al Kharusi A; Norstedt G.
      Abstract: Background: Increased levels of Prolactin (Prl) receptors have been found in endocrine dependent cancers e.g. breast and prostate cancer as well as in ovarian cancer and glioblastomas. Prl stimulates cell growth by activating the intracellular JAK-STAT pathway. A new line of research in the last years suggest that human cytomegalovirus (CMV) infection can also contribute to several human malignancies including glioblastoma brain tumor and ovarian cancer. A supportive study, showed that CMV DNA was present in 50% of fresh ovarian carcinoma tissue samples (39 samples). It was suggested that human CMV is able to create a more malignant phenotype of tumor cells by the action of its regulatory proteins and non-coding RNA, which will affect their proliferation, invasion of other tissues, survival and other cellular properties. Furthermore, prolactin receptor expression and circulating prolactin levels have been shown to be higher among women with ovarian cancer vs. benign-condition or healthy control.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.046
       
  • 99PEffective model for antitumor drugs screening based on 3D growth system
           of MCF-7
    • Authors: Nikolaienko T; Garmanchuk L, Stupak Y.
      Abstract: Background: Gene expression profiles in spheroid cultivated cells are more similar to natural tumors, than profiles of the same cells in monolayer culture. Tumor spheroids are heterogeneous cellular aggregates that, when greater than 500 μm diameter, are frequently characterized by hypoxic regions and necrotic centers. Architecture of three-dimensionally (3D) propagated cells is very similar to avascular tumor areas. The gradient of diffusion in cell aggregates leads to reduced proliferation rates and increased drug resistance. The purpose of the work was to conduct a comparative study between 3D and monolayer growth systems of MCF-7 cells, and prove the value of spheroid model.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy047.047
       
  • 9IN4SC-202 plus anti-PD1: Breaking PD1-refractoriness to increase efficacy
           of checkpoint inhibition in patients with advanced melanoma
    • Authors: Bartz R.
      Abstract: Background: Despite successes in the treatment of melanoma patients with checkpoint inhibitors (CI), most patients do not respond to CI alone and a high unmet medical need remains for these patients. One promising approach is to enhance the immunogenicity and alter the tumor microenvironment from a more immune-deserted to an immune-inflamed phenotype by means of combination therapy. Epigenetic modulation has been reported as one key determining factor in shaping the immune microenvironment and compounds altering these processes (e.g. histone deacetylases (HDAC) inhibitors) are particularly promising.
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy046.003
       
  • TAT 2018 Drug Index
    • Abstract: 1-D-MT: 87P
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy078
       
  • TAT 2018 Translational Research Index
    • Abstract: 4EBP1: 70P
      PubDate: Mon, 05 Mar 2018 00:00:00 GMT
      DOI: 10.1093/annonc/mdy079
       
 
 
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