565 Preclinical evaluation of OTX015, a novel BET-BRD inhibitor, on small cell lung cancer (SCLC) cell lines

Ijaz, Nadia; Astorgues‐Xerri, Lucile; Odore, Elodie; Bekradda, M.; Cvitkovic, Esteban; Noel, Kay; Raymond, Éric; Riveiro, María E.

doi:10.1016/s0959-8049(14)70691-4

European Journal of Cancer

2014

DOI: 10.1016/s0959-8049(14)70691-4

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565 Preclinical evaluation of OTX015, a novel BET-BRD inhibitor, on small cell lung cancer (SCLC) cell lines

Nadia Ijaz¹,

Lucile Astorgues‐Xerri²,

Elodie Odore³

et al.

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“…A number of preclinical studies have been performed in GBM models with BRD inhibitors, JQ1 and I‐BET151, showing promising antitumor activity . Another BRD inhibitor, OTX015 (MK‐8628), has shown remarkable and selective potency against BRD2/3/4 in vitro as well as in vivo antitumor activity, in a range of tumor models including leukemia, lymphoma, myeloma, neuroblastoma, lung cancer, and triple negative breast cancer . OTX015 is the first BRD inhibitor to have moved into the clinic, with a first‐in‐man phase Ib study in patients with hematologic malignancies (NCT01713582).…”

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confidence: 99%

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

Berenguer-Daizé

Astorgues‐Xerri²,

Odore

et al. 2016

Intl Journal of Cancer

123

102

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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 GI 50 values of approximately 0.2 mM. 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.Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in humans, accounting for 52% of all functional tissue brain tumors and 20% of all intracranial tumors. 1,2 Standard of care is typically surgery followed by radiotherapy with the DNA alkylating agent temozolomide. 3 Median survival after diagnosis is only 15 months, leaving a large unmet medical need. 4 Alternative therapeutic approaches have focused on targeted therapies against processes known to play a major role in GBM development, such as blocking angiogenesis with the anti-VEGF agent, bevacizumab. 5 The topoisomerase inhibitor irinotecan which blocks DNA replication causing cell death has also shown hints of activity against malignant glioma in the clinical setting. 6,7 Key words: BET inhibitor, OTX015 (MK-8628), glioblastoma, blood brain barrier, combination studies. Abbreviations: 95% CI: 95% confidence interval; BET: bromodomain and extraterminal; BID: bi-daily; BRD: bromodomain; CI: combination index; E max : drug efficacy as percent cell proliferation inhibition at the highest dose; GBM: glioblastoma multiforme; GI 50 : drug concentration at which cell proliferation is reduced by half; IP: intraperitoneal; MTX: methotrexate; po: per orally; VEGF: vascula...

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mentioning

confidence: 99%

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

Berenguer-Daizé

Astorgues‐Xerri²,

Odore

et al. 2016

Intl Journal of Cancer

123

102

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565 Preclinical evaluation of OTX015, a novel BET-BRD inhibitor, on small cell lung cancer (SCLC) cell lines

Cited by 1 publication

References 0 publications

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

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

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