title: OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models.
abstract: Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines. OTX015 displayed higher antiproliferative effects compared to its analog JQ1, with GI50 values of approximately 0.2 µM. In addition, C-MYC and CDKN1A mRNA levels increased transiently after 4 h-exposure to OTX015, while BRD2, SESN3, HEXIM-1, HIST2H2BE, and HIST1H2BK were rapidly upregulated and sustained after 24 h. Studies in three additional GBM cell lines supported the antiproliferative effects of OTX015. In U87MG cells, OTX015 showed synergistic to additive activity when administered concomitant to or before SN38, temozolomide or everolimus. Single agent oral OTX015 significantly increased survival in mice bearing orthotopic or heterotopic U87MG xenografts. OTX015 combined simultaneously with temozolomide improved mice survival over either single agent. The passage of OTX015 across the blood-brain barrier was demonstrated with OTX015 tumor levels 7 to 15-fold higher than in normal tissues, along with preferential binding of OTX015 to tumor tissue. The significant antitumor effects seen with OTX015 in GBM xenograft models highlight its therapeutic potential in GBM patients, alone or combined with conventional chemotherapies.
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Marseille, 13385, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Berenguer-Daizé
authors.affiliation: Oncology Therapeutic Development, 100 Rue Martre, Clichy, 92110, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Astorgues-Xerri
authors.affiliation: Oncology Therapeutic Development, 100 Rue Martre, Clichy, 92110, France.|Department of Radio-Pharmacology, Institut Curie, René Huguenin Hospital, 35 Rue Daily, Saint-Cloud, 92210, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Odore
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Marseille, 13385, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Cayol
authors.affiliation: Oncology Therapeutic Development, 100 Rue Martre, Clichy, 92110, France.|Oncoethix SA (Now Oncoethix GmbH, a Wholly Owned Subsidiary of Merck Sharp and Dohme Corp.), Weystrasse 20, Lucerne, 6000, Switzerland.
authors.forename: Esteban
authors.initials: E
authors.lastname: Cvitkovic
authors.affiliation: Oncoethix SA (Now Oncoethix GmbH, a Wholly Owned Subsidiary of Merck Sharp and Dohme Corp.), Weystrasse 20, Lucerne, 6000, Switzerland.
authors.forename: Kay
authors.initials: K
authors.lastname: Noel
authors.affiliation: Oncology Therapeutic Development, 100 Rue Martre, Clichy, 92110, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bekradda
authors.affiliation: Oncology Therapeutic Development, 100 Rue Martre, Clichy, 92110, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: MacKenzie
authors.affiliation: Department of Radio-Pharmacology, Institut Curie, René Huguenin Hospital, 35 Rue Daily, Saint-Cloud, 92210, France.
authors.forename: Keyvan
authors.initials: K
authors.lastname: Rezai
authors.affiliation: Department of Radio-Pharmacology, Institut Curie, René Huguenin Hospital, 35 Rue Daily, Saint-Cloud, 92210, France.
authors.forename: François
authors.initials: F
authors.lastname: Lokiec
authors.affiliation: Oncology Therapeutic Development, 100 Rue Martre, Clichy, 92110, France.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Riveiro
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Marseille, 13385, France.
authors.forename: L'Houcine
authors.initials: L
authors.lastname: Ouafik
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D000068338:Everolimus / Q000008:administration & dosage / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy*; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D000083:Acetanilides; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C000605331:OTX015; D000077146:Irinotecan; D003606:Dacarbazine; D000068338:Everolimus; D002166:Camptothecin; D000077204:Temozolomide
keywords: BET inhibitor; OTX015 (MK-8628); blood brain barrier; combination studies; glioblastoma