1. Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK-8628 in malignant pleural mesothelioma xenografts
- Author
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Ramiro, Vázquez, Simonetta Andrea, Licandro, Lucile, Astorgues-Xerri, Emanuele, Lettera, Nicolò, Panini, Michela, Romano, Eugenio, Erba, Paolo, Ubezio, Ezia, Bello, Roberta, Libener, Sara, Orecchia, Federica, Grosso, María Eugenia, Riveiro, Esteban, Cvitkovic, Mohamed, Bekradda, Maurizio, D'Incalci, Roberta, Frapolli, Vazquez, R, Licandro, S, Astorgues-Xerri, L, Lettera, E, Panini, N, Romano, M, Erba, E, Ubezio, P, Bello, E, Libener, R, Orecchia, S, Grosso, F, Riveiro, M, Cvitkovic, E, Bekradda, M, D'Incalci, M, and Frapolli, R
- Subjects
Male ,Mesothelioma ,Lung Neoplasms ,Cell Survival ,Mesothelioma, Malignant ,Down-Regulation ,Pemetrexed ,Middle Aged ,Deoxycytidine ,Xenograft Model Antitumor Assays ,Gemcitabine ,bromodomain inhibitor, mesothelioma, MYC downregulation, OTX015/MK-8628, Acetanilides, Aged, Animals, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cisplatin, Deoxycytidine, Down-Regulation, Female, Gene Expression Regulation, Neoplastic, Heterocyclic Compounds, 3-Ring, Humans, Lung Neoplasms, Male, Mesothelioma, Mice, Middle Aged, Pemetrexed, Proto-Oncogene Proteins c-myc, Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Proto-Oncogene Proteins c-myc ,Mice ,Cell Line, Tumor ,Animals ,Humans ,Acetanilides ,Female ,Cisplatin ,Heterocyclic Compounds, 3-Ring ,Aged ,Cell Proliferation - Abstract
It has recently been reported that a large proportion of human malignant pleural mesothelioma (MPM) cell lines and patient tissue samples present high expression of the c-MYC oncogene. This gene drives several tumorigenic processes and is overexpressed in many cancers. Although c-MYC is a strategic target to restrain cancer processes, no drugs acting as c-MYC inhibitors are available. The novel thienotriazolodiazepine small-molecule bromodomain inhibitor OTX015/MK-8628 has shown potent antiproliferative activity accompanied by c-MYC downregulation in several tumor types. This study was designed to evaluate the growth inhibitory effect of OTX015 on patient-derived MPM473, MPM487 and MPM60 mesothelioma cell lines and its antitumor activity in three patient-derived xenograft models, MPM473, MPM487 and MPM484, comparing it with cisplatin, gemcitabine and pemetrexed, three agents which are currently used to treat MPM in the clinic. OTX015 caused a significant delay in cell growth both in vitro and in vivo. It was the most effective drug in MPM473 xenografts and showed a similar level of activity as the most efficient treatment in the other two MPM models (gemcitabine in MPM487 and cisplatin in MPM484). In vitro studies showed that OTX015 downregulated c-MYC protein levels in both MPM473 and MPM487 cell lines. Our findings represent the first evidence of promising therapeutic activity of OTX015 in mesothelioma.
- Published
- 2017