title: XRP44X, an Inhibitor of Ras/Erk Activation of the Transcription Factor Elk3, Inhibits Tumour Growth and Metastasis in Mice.
abstract: Transcription factors have an important role in cancer but are difficult targets for the development of tumour therapies. These factors include the Ets family, and in this study Elk3 that is activated by Ras oncogene /Erk signalling, and is involved in angiogenesis, malignant progression and epithelial-mesenchymal type processes. We previously described the identification and in-vitro characterisation of an inhibitor of Ras / Erk activation of Elk3 that also affects microtubules, XRP44X. We now report an initial characterisation of the effects of XRP44X in-vivo on tumour growth and metastasis in three preclinical models mouse models, subcutaneous xenografts, intra-cardiac injection-bone metastasis and the TRAMP transgenic mouse model of prostate cancer progression. XRP44X inhibits tumour growth and metastasis, with limited toxicity. Tumours from XRP44X-treated animals have decreased expression of genes containing Elk3-like binding motifs in their promoters, Elk3 protein and phosphorylated Elk3, suggesting that perhaps XRP44X acts in part by inhibiting the activity of Elk3. Further studies are now warranted to develop XRP44X for tumour therapy.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Kostyantyn
authors.initials: K
authors.lastname: Semenchenko
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Wasylyk
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Henry
authors.initials: H
authors.lastname: Cheung
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Tourrette
authors.affiliation: SPECS, Kluyverweg 6, 2629 HT Delft, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Maas
authors.affiliation: Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Schalken
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Gabri
authors.initials: G
authors.lastname: van der Pluijm
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Bohdan
authors.identifier: http://orcid.org/0000-0002-1718-1237
authors.initials: B
authors.lastname: Wasylyk
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000187:drug effects; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D008870:Microtubules / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050783:Proto-Oncogene Proteins c-ets / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C086924:Elk3 protein, mouse; D010879:Piperazines; D050783:Proto-Oncogene Proteins c-ets; D011720:Pyrazoles; C527882:XRP44X compound; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3