nach oben

Erschienen in:

05.01.2017 | PRECLINICAL STUDIES

Zebrafish phenotypic screen identifies novel Notch antagonists

verfasst von: Vithya Velaithan, Kazuhide Shaun Okuda, Mei Fong Ng, Norazwana Samat, Sze Wei Leong, Siti Munirah Mohd Faudzi, Faridah Abas, Khozirah Shaari, Sok Ching Cheong, Pei Jean Tan, Vyomesh Patel

Erschienen in: Investigational New Drugs | Ausgabe 2/2017

Einloggen, um Zugang zu erhalten

Summary

Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G₀/G₁ cell cycle arrest of ORL-150 cells through inducing p27^KIP1. Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.

Nur mit Berechtigung zugänglich

Stern HM, Zon LI (2003) Cancer genetics and drug discovery in the zebrafish. Nat Rev Cancer 3(7):533–539. doi:10.1038/nrc1126 CrossRefPubMed

Mione MC, Trede NS (2010) The zebrafish as a model for cancer. Dis Models Mech 3(9–10):517–523. doi:10.1242/dmm.004747 CrossRef

Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C, Muffato M, Collins JE, Humphray S, McLaren K, Matthews L, McLaren S, Sealy I, Caccamo M, Churcher C, Scott C, Barrett JC, Koch R, Rauch GJ, White S, Chow W, Kilian B, Quintais LT, Guerra-Assuncao JA, Zhou Y, Gu Y, Yen J, Vogel JH, Eyre T, Redmond S, Banerjee R, Chi J, Fu B, Langley E, Maguire SF, Laird GK, Lloyd D, Kenyon E, Donaldson S, Sehra H, Almeida-King J, Loveland J, Trevanion S, Jones M, Quail M, Willey D, Hunt A, Burton J, Sims S, McLay K, Plumb B, Davis J, Clee C, Oliver K, Clark R, Riddle C, Elliot D, Threadgold G, Harden G, Ware D, Begum S, Mortimore B, Kerry G, Heath P, Phillimore B, Tracey A, Corby N, Dunn M, Johnson C, Wood J, Clark S, Pelan S, Griffiths G, Smith M, Glithero R, Howden P, Barker N, Lloyd C, Stevens C, Harley J, Holt K, Panagiotidis G, Lovell J, Beasley H, Henderson C, Gordon D, Auger K, Wright D, Collins J, Raisen C, Dyer L, Leung K, Robertson L, Ambridge K, Leongamornlert D, McGuire S, Gilderthorp R, Griffiths C, Manthravadi D, Nichol S, Barker G, Whitehead S, Kay M, Brown J, Murnane C, Gray E, Humphries M, Sycamore N, Barker D, Saunders D, Wallis J, Babbage A, Hammond S, Mashreghi-Mohammadi M, Barr L, Martin S, Wray P, Ellington A, Matthews N, Ellwood M, Woodmansey R, Clark G, Cooper J, Tromans A, Grafham D, Skuce C, Pandian R, Andrews R, Harrison E, Kimberley A, Garnett J, Fosker N, Hall R, Garner P, Kelly D, Bird C, Palmer S, Gehring I, Berger A, Dooley CM, Ersan-Urun Z, Eser C, Geiger H, Geisler M, Karotki L, Kirn A, Konantz J, Konantz M, Oberlander M, Rudolph-Geiger S, Teucke M, Lanz C, Raddatz G, Osoegawa K, Zhu B, Rapp A, Widaa S, Langford C, Yang F, Schuster SC, Carter NP, Harrow J, Ning Z, Herrero J, Searle SM, Enright A, Geisler R, Plasterk RH, Lee C, Westerfield M, de Jong PJ, Zon LI, Postlethwait JH, Nusslein-Volhard C, Hubbard TJ, Roest Crollius H, Rogers J, Stemple DL (2013) The zebrafish reference genome sequence and its relationship to the human genome. Nature 496(7446):498–503. doi:10.1038/nature12111 CrossRefPubMedPubMedCentral

Geissler K, Zach O (2012) Pathways involved in Drosophila and human cancer development: the Notch, Hedgehog, Wingless, Runt, and Trithorax pathway. Ann Hematol 91(5):645–669. doi:10.1007/s00277-012-1435-0 CrossRefPubMed

Kelleher FC, Fennelly D, Rafferty M (2006) Common critical pathways in embryogenesis and cancer. Acta Oncol 45(4):375–388. doi:10.1080/02841860600602946 CrossRefPubMed

Rida PC, Le Minh N, Jiang YJ (2004) A Notch feeling of somite segmentation and beyond. Dev Biol 265(1):2–22CrossRefPubMed

Jiang YJ, Brand M, Heisenberg CP, Beuchle D, Furutani-Seiki M, Kelsh RN, Warga RM, Granato M, Haffter P, Hammerschmidt M, Kane DA, Mullins MC, Odenthal J, van Eeden FJ, Nusslein-Volhard C (1996) Mutations affecting neurogenesis and brain morphology in the zebrafish, Danio rerio. Development 123:205–216PubMed

van Eeden FJ, Granato M, Schach U, Brand M, Furutani-Seiki M, Haffter P, Hammerschmidt M, Heisenberg CP, Jiang YJ, Kane DA, Kelsh RN, Mullins MC, Odenthal J, Warga RM, Allende ML, Weinberg ES, Nusslein-Volhard C (1996) Mutations affecting somite formation and patterning in the zebrafish, Danio rerio. Development 123:153–164PubMed

Geling A, Steiner H, Willem M, Bally-Cuif L, Haass C (2002) A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep 3(7):688–694. doi:10.1093/embo-reports/kvf124 CrossRefPubMedPubMedCentral

10.

Ozbudak EM, Lewis J (2008) Notch signalling synchronizes the zebrafish segmentation clock but is not needed to create somite boundaries. PLoS Genet 4(2):e15. doi:10.1371/journal.pgen.0040015 CrossRefPubMedPubMedCentral

11.

Arslanova D, Yang T, Xu X, Wong ST, Augelli-Szafran CE, Xia W (2010) Phenotypic analysis of images of zebrafish treated with Alzheimer’s gamma-secretase inhibitors. BMC Biotechnol 10:24. doi:10.1186/1472-6750-10-24 CrossRefPubMedPubMedCentral

12.

Penton AL, Leonard LD, Spinner NB (2012) Notch signaling in human development and disease. Semin Cell Dev Biol 23(4):450–457. doi:10.1016/j.semcdb.2012.01.010 CrossRefPubMedPubMedCentral

13.

Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306(5694):269–271. doi:10.1126/science.1102160 CrossRefPubMed

14.

Purow BW, Haque RM, Noel MW, Su Q, Burdick MJ, Lee J, Sundaresan T, Pastorino S, Park JK, Mikolaenko I, Maric D, Eberhart CG, Fine HA (2005) Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res 65(6):2353–2363. doi:10.1158/0008-5472.CAN-04-1890 CrossRefPubMed

15.

Sun W, Gaykalova DA, Ochs MF, Mambo E, Arnaoutakis D, Liu Y, Loyo M, Agrawal N, Howard J, Li R, Ahn S, Fertig E, Sidransky D, Houghton J, Buddavarapu K, Sanford T, Choudhary A, Darden W, Adai A, Latham G, Bishop J, Sharma R, Westra WH, Hennessey P, Chung CH, Califano JA (2014) Activation of the NOTCH pathway in head and neck cancer. Cancer Res 74(4):1091–1104. doi:10.1158/0008-5472.CAN-13-1259 CrossRefPubMed

16.

Sjolund J, Johansson M, Manna S, Norin C, Pietras A, Beckman S, Nilsson E, Ljungberg B, Axelson H (2008) Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo. J Clin Invest 118(1):217–228. doi:10.1172/JCI32086 CrossRefPubMed

17.

Hu W, Lu C, Dong HH, Huang J, Shen DY, Stone RL, Nick AM, Shahzad MM, Mora E, Jennings NB, Lee SJ, Roh JW, Matsuo K, Nishimura M, Goodman BW, Jaffe RB, Langley RR, Deavers MT, Lopez-Berestein G, Coleman RL, Sood AK (2011) Biological roles of the Delta family Notch ligand Dll4 in tumor and endothelial cells in ovarian cancer. Cancer Res 71(18):6030–6039. doi:10.1158/0008-5472.CAN-10-2719 CrossRefPubMedPubMedCentral

18.

Jubb AM, Miller KD, Rugo HS, Harris AL, Chen D, Reimann JD, Cobleigh MA, Schmidt M, Langmuir VK, Hillan KJ, Chen DS, Koeppen H (2011) Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer. Clin Cancer Res 17(2):372–381. doi:10.1158/1078-0432.CCR-10-1791 CrossRefPubMedPubMedCentral

19.

Takebe N, Nguyen D, Yang SX (2014) Targeting notch signaling pathway in cancer: clinical development advances and challenges. Pharmacol Ther 141(2):140–149. doi:10.1016/j.pharmthera.2013.09.005 CrossRefPubMed

20.

Yuan X, Wu H, Xu H, Xiong H, Chu Q, Yu S, Wu GS, Wu K (2015) Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett 369(1):20–27. doi:10.1016/j.canlet.2015.07.048 CrossRefPubMed

21.

Krop I, Demuth T, Guthrie T, Wen PY, Mason WP, Chinnaiyan P, Butowski N, Groves MD, Kesari S, Freedman SJ, Blackman S, Watters J, Loboda A, Podtelezhnikov A, Lunceford J, Chen C, Giannotti M, Hing J, Beckman R, Lorusso P (2012) Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. Clin Oncol Off J Am Soc Clin Oncol 30(19):2307–2313. doi:10.1200/JCO.2011.39.1540 CrossRef

22.

De Jesus-Acosta A, Laheru D, Maitra A, Arcaroli J, Rudek MA, Dasari A, Blatchford PJ, Quackenbush K, Messersmith W (2014) A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma. Investig New Drugs 32(4):739–745. doi:10.1007/s10637-014-0083-8 CrossRef

23.

Hughes DP, Kummar S, Lazar AJ (2015) New, tolerable gamma-secretase inhibitor takes desmoid down a notch. Clin Cancer Res 21(1):7–9. doi:10.1158/1078-0432.CCR-14-1660 CrossRefPubMed

24.

Tolcher AW, Messersmith WA, Mikulski SM, Papadopoulos KP, Kwak EL, Gibbon DG, Patnaik A, Falchook GS, Dasari A, Shapiro GI, Boylan JF, Xu ZX, Wang K, Koehler A, Song J, Middleton SA, Deutsch J, Demario M, Kurzrock R, Wheler JJ (2012) Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol Off J Am Soc Clin Oncol 30(19):2348–2353. doi:10.1200/JCO.2011.36.8282 CrossRef

25.

Cragg GM, Newman DJ (2013) Natural products: a continuing source of novel drug leads. Biochim Biophys Acta 1830(6):3670–3695. doi:10.1016/j.bbagen.2013.02.008 CrossRefPubMedPubMedCentral

26.

Leong SW, Abas F, Lam KW, Shaari K, Lajis NH (2016) 2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase. Bioorg Med Chem 24(16):3742–3751. doi:10.1016/j.bmc.2016.06.016 CrossRefPubMed

27.

Dou Y, Andersson-Lendahl M, Arner A (2008) Structure and function of skeletal muscle in zebrafish early larvae. J Gen Physiol 131(5):445–453. doi:10.1085/jgp.200809982 CrossRefPubMedPubMedCentral

28.

Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF (1995) Stages of embryonic development of the zebrafish. Dev Dyn 203(3):253–310. doi:10.1002/aja.1002030302 CrossRefPubMed

29.

Fadlullah MZ, Chiang IK, Dionne KR, Yee PS, Gan CP, Sam KK, Tiong KH, Wen Ng AK, Martin D, Lim KP, Kallarakkal TG, Wan Mustafa WM, Lau SH, Abraham MT, Zain RB, Abdul Rahman ZA, Molinolo A, Patel V, Gutkind JS, Tan AC, Cheong SC (2016) Genetically-defined novel oral squamous cell carcinoma cell lines for the development of molecular therapies. Oncotarget 7(19):27802–27818. doi:10.18632/oncotarget.8533 PubMedPubMedCentral

30.

Gan CP, Patel V, Mikelis CM, Zain RB, Molinolo AA, Abraham MT, Teo SH, Abdul Rahman ZA, Gutkind JS, Cheong SC (2014) Heterotrimeric G-protein alpha-12 (Galpha12) subunit promotes oral cancer metastasis. Oncotarget 5(20):9626–9640. doi:10.18632/oncotarget.2437 CrossRefPubMedPubMedCentral

31.

Sail V, Hadden MK (2013) Identification of small molecule Hes1 modulators as potential anticancer chemotherapeutics. Chem Biol Drug Des 81(3):334–342. doi:10.1111/cbdd.12059 CrossRefPubMed

32.

Brady CA, Rennekamp AJ, Peterson RT (2016) Chemical Screening in Zebrafish. Methods Mol Biol 1451:3–16. doi:10.1007/978-1-4939-3771-4_1 CrossRefPubMed

33.

Borggrefe T, Oswald F (2009) The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci 66(10):1631–1646. doi:10.1007/s00018-009-8668-7 CrossRefPubMed

34.

Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J, Zhang N, El-Naggar AK, Jasser SA, Weinstein JN, Trevino L, Drummond JA, Muzny DM, Wu Y, Wood LD, Hruban RH, Westra WH, Koch WM, Califano JA, Gibbs RA, Sidransky D, Vogelstein B, Velculescu VE, Papadopoulos N, Wheeler DA, Kinzler KW, Myers JN (2011) Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333(6046):1154–1157. doi:10.1126/science.1206923 CrossRefPubMedPubMedCentral

35.

Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, Kryukov GV, Lawrence MS, Sougnez C, McKenna A, Shefler E, Ramos AH, Stojanov P, Carter SL, Voet D, Cortes ML, Auclair D, Berger MF, Saksena G, Guiducci C, Onofrio RC, Parkin M, Romkes M, Weissfeld JL, Seethala RR, Wang L, Rangel-Escareno C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Winckler W, Ardlie K, Gabriel SB, Meyerson M, Lander ES, Getz G, Golub TR, Garraway LA, Grandis JR (2011) The mutational landscape of head and neck squamous cell carcinoma. Science 333(6046):1157–1160. doi:10.1126/science.1208130 CrossRefPubMedPubMedCentral

36.

Pickering CR, Zhang J, Yoo SY, Bengtsson L, Moorthy S, Neskey DM, Zhao M, Ortega Alves MV, Chang K, Drummond J, Cortez E, Xie TX, Zhang D, Chung W, Issa JP, Zweidler-McKay PA, Wu X, El-Naggar AK, Weinstein JN, Wang J, Muzny DM, Gibbs RA, Wheeler DA, Myers JN, Frederick MJ (2013) Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Disc 3(7):770–781. doi:10.1158/2159-8290.CD-12-0537 CrossRef

37.

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:10.1016/j.cell.2011.02.013 CrossRefPubMed

38.

Ranganathan P, Weaver KL, Capobianco AJ (2011) Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer 11(5):338–351. doi:10.1038/nrc3035 CrossRefPubMed

39.

Ridges S, Heaton WL, Joshi D, Choi H, Eiring A, Batchelor L, Choudhry P, Manos EJ, Sofla H, Sanati A, Welborn S, Agarwal A, Spangrude GJ, Miles RR, Cox JE, Frazer JK, Deininger M, Balan K, Sigman M, Muschen M, Perova T, Johnson R, Montpellier B, Guidos CJ, Jones DA, Trede NS (2012) Zebrafish screen identifies novel compound with selective toxicity against leukemia. Blood 119(24):5621–5631. doi:10.1182/blood-2011-12-398818 CrossRefPubMedPubMedCentral

40.

Bentley VL, Veinotte CJ, Corkery DP, Pinder JB, LeBlanc MA, Bedard K, Weng AP, Berman JN, Dellaire G (2015) Focused chemical genomics using zebrafish xenotransplantation as a pre-clinical therapeutic platform for T-cell acute lymphoblastic leukemia. Haematologica 100(1):70–76. doi:10.3324/haematol.2014.110742 CrossRefPubMedPubMedCentral

41.

MacRae CA, Peterson RT (2015) Zebrafish as tools for drug discovery. Nat Rev Drug Discov 14(10):721–731. doi:10.1038/nrd4627 CrossRefPubMed

42.

Wheeler GN, Brandli AW (2009) Simple vertebrate models for chemical genetics and drug discovery screens: lessons from zebrafish and Xenopus. Dev Dyn 238(6):1287–1308. doi:10.1002/dvdy.21967 CrossRefPubMed

43.

Dreesen O, Brivanlou AH (2007) Signaling pathways in cancer and embryonic stem cells. Stem Cell Rev 3(1):7–17CrossRefPubMed

44.

Astudillo L, Da Silva TG, Wang Z, Han X, Jin K, VanWye J, Zhu X, Weaver K, Oashi T, Lopes PE, Orton D, Neitzel LR, Lee E, Landgraf R, Robbins DJ, MacKerell AD Jr, Capobianco AJ (2016) The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis. Cancer Res 76(12):3593–3603. doi:10.1158/0008-5472.CAN-16-0061 CrossRefPubMed

45.

Shelton CC, Tian Y, Frattini MG, Li YM (2009) An exo-cell assay for examining real-time gamma-secretase activity and inhibition. Mol Neurodegener 4:22. doi:10.1186/1750-1326-4-22 CrossRefPubMedPubMedCentral

46.

North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord AM, Weber GJ, Bowman TV, Jang IH, Grosser T, Fitzgerald GA, Daley GQ, Orkin SH, Zon LI (2007) Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 447(7147):1007–1011. doi:10.1038/nature05883 CrossRefPubMedPubMedCentral

47.

Yu PB, Hong CC, Sachidanandan C, Babitt JL, Deng DY, Hoyng SA, Lin HY, Bloch KD, Peterson RT (2008) Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol 4(1):33–41. doi:10.1038/nchembio.2007.54 CrossRefPubMed

48.

Owens KN, Santos F, Roberts B, Linbo T, Coffin AB, Knisely AJ, Simon JA, Rubel EW, Raible DW (2008) Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death. PLoS Genet 4(2):e1000020. doi:10.1371/journal.pgen.1000020 CrossRefPubMedPubMedCentral

49.

Kageyama R, Niwa Y, Isomura A, Gonzalez A, Harima Y (2012) Oscillatory gene expression and somitogenesis. Wiley Interdiscip Rev Dev Biol 1(5):629–641. doi:10.1002/wdev.46 CrossRefPubMed

50.

Schreck KC, Taylor P, Marchionni L, Gopalakrishnan V, Bar EE, Gaiano N, Eberhart CG (2010) The Notch target Hes1 directly modulates Gli1 expression and Hedgehog signaling: a potential mechanism of therapeutic resistance. Clin Cancer Res 16(24):6060–6070. doi:10.1158/1078-0432.CCR-10-1624 CrossRefPubMedPubMedCentral

51.

Liu ZH, Dai XM, Du B (2015) Hes1: a key role in stemness, metastasis and multidrug resistance. Cancer Biol Ther 16(3):353–359. doi:10.1080/15384047.2015.1016662 CrossRefPubMedPubMedCentral

52.

Abravanel DL, Belka GK, Pan TC, Pant DK, Collins MA, Sterner CJ, Chodosh LA (2015) Notch promotes recurrence of dormant tumor cells following HER2/neu-targeted therapy. J Clin Invest 125(6):2484–2496. doi:10.1172/JCI74883 CrossRefPubMedPubMedCentral

53.

Golan T, Messer AR, Amitai-Lange A, Melamed Z, Ohana R, Bell RE, Kapitansky O, Lerman G, Greenberger S, Khaled M, Amar N, Albrengues J, Gaggioli C, Gonen P, Tabach Y, Sprinzak D, Shalom-Feuerstein R, Levy C (2015) Interactions of Melanoma Cells with Distal Keratinocytes Trigger Metastasis via Notch Signaling Inhibition of MITF. Mol Cell 59(4):664–676. doi:10.1016/j.molcel.2015.06.028 CrossRefPubMed

54.

Rao SS, O’Neil J, Liberator CD, Hardwick JS, Dai X, Zhang T, Tyminski E, Yuan J, Kohl NE, Richon VM, Van der Ploeg LH, Carroll PM, Draetta GF, Look AT, Strack PR, Winter CG (2009) Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells. Cancer Res 69(7):3060–3068. doi:10.1158/0008-5472.CAN-08-4295 CrossRefPubMed

55.

Crown J (2001) Docetaxel: overview of an active drug for breast cancer. Oncologist 6(Suppl 3):1–4CrossRefPubMed

56.

Parsons MJ, Pisharath H, Yusuff S, Moore JC, Siekmann AF, Lawson N, Leach SD (2009) Notch-responsive cells initiate the secondary transition in larval zebrafish pancreas. Mech Dev 126(10):898–912. doi:10.1016/j.mod.2009.07.002 CrossRefPubMedPubMedCentral

57.

Schiavone M, Rampazzo E, Casari A, Battilana G, Persano L, Moro E, Liu S, Leach SD, Tiso N, Argenton F (2014) Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer. Dis Models Mech 7(7):883–894. doi:10.1242/dmm.014969 CrossRef

58.

Henkel T, Ling PD, Hayward SD, Peterson MG (1994) Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa. Science 265(5168):92–95CrossRefPubMed

Titel: Zebrafish phenotypic screen identifies novel Notch antagonists
verfasst von: Vithya Velaithan
Kazuhide Shaun Okuda
Mei Fong Ng
Norazwana Samat
Sze Wei Leong
Siti Munirah Mohd Faudzi
Faridah Abas
Khozirah Shaari
Sok Ching Cheong
Pei Jean Tan
Vyomesh Patel
Publikationsdatum: 05.01.2017
Verlag: Springer US
Erschienen in: Investigational New Drugs / Ausgabe 2/2017
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-016-0423-y

Springer Medizin

Zebrafish phenotypic screen identifies novel Notch antagonists

Summary

Neu im Fachgebiet Onkologie

Erhöhte Mortalität bei postpartalem Brustkrebs

Hypertherme Chemotherapie bietet Chance auf Blasenerhalt

Ein Drittel der jungen Ärztinnen und Ärzte erwägt abzuwandern

Bessere Prognose mit links- statt rechtsseitigem Kolon-Ca.

Update Onkologie

Springer Medizin

Summary

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2017

Erlotinib pharmacokinetics: a critical parameter influencing acute toxicity in elderly patients over 75 years-old

A phase II study of carboplatin plus weekly paclitaxel with bevacizumab for elderly patients with non-squamous non-small-cell lung cancer (NEJ016)

A phase 1 study of the pharmacokinetics of nucleoside analog trifluridine and thymidine phosphorylase inhibitor tipiracil (components of TAS-102) vs trifluridine alone

Erratum to: Zebrafish phenotypic screen identifies novel Notch antagonists

Phase II study of the antibody-drug conjugate TAK-264 (MLN0264) in patients with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction expressing guanylyl cyclase C

Alofanib, an allosteric FGFR2 inhibitor, has potent effects on ovarian cancer growth in preclinical studies

Neu im Fachgebiet Onkologie

Erhöhte Mortalität bei postpartalem Brustkrebs

Hypertherme Chemotherapie bietet Chance auf Blasenerhalt

Ein Drittel der jungen Ärztinnen und Ärzte erwägt abzuwandern

Bessere Prognose mit links- statt rechtsseitigem Kolon-Ca.

Update Onkologie