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.

Vazquez, R., Licandro, S., Astorgues-Xerri, L., Lettera, E., Panini, N., Romano, M., et al. (2017). Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK-8628 in malignant pleural mesothelioma xenografts. INTERNATIONAL JOURNAL OF CANCER, 140(1), 197-207 [10.1002/ijc.30412].

Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK-8628 in malignant pleural mesothelioma xenografts

Licandro S. A.;
2017

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.
Articolo in rivista - Articolo scientifico
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
English
2017
140
1
197
207
none
Vazquez, R., Licandro, S., Astorgues-Xerri, L., Lettera, E., Panini, N., Romano, M., et al. (2017). Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK-8628 in malignant pleural mesothelioma xenografts. INTERNATIONAL JOURNAL OF CANCER, 140(1), 197-207 [10.1002/ijc.30412].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/280740
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