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 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...

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

“…The Brd4 inhibitor JQ1 suppressed iNOS expression, NO production, and cell hyper-aggressiveness much more powerfully than an inhibitor of iNOS enzymatic activity, suggesting that JQ1 or a related BET bromodomain inhibitor could greatly improve clinical PDT outcomes for glioblastoma and possibly other malignancies. A few examples of combining JQ1 with conventional radio-or chemotherapeutic approaches have been reported (54,77,78), but the present study represents the first time that JQ1 has been combined with PDT, which is recognized as one of the best treatment options for many solid tumors, including glioblastomas (67)(68)(69). Our findings from this in vitro study provide a strong incentive for more advanced work involving JQ1 in a mouse tumor PDT model, which will soon be underway.…”

“…Numerous other examples of combining BET bromodomain inhibitors with conventional chemotherapeutic agents have been described recently, e.g. JQ1 with paclitaxel for triple negative breast cancer (77), and OTX015 with temozolomide for glioblastoma (78). A potential clinical advantage of such combined treatments is that lower than normal individual drug dosages can be used, thus causing less off-target toxicity.…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…As an example, OTX015 crosses the blood-brain barrier and selectively penetrates tumor tissue. 133 OTX015 tumor levels were 7-15 times higher than in normal brain tissues in several in vivo models. 133 As another example, GSK-J4 brain access has been assessed in murine DIPG models, after being administered to mice by intraperitoneal injection.…”

“…133 OTX015 tumor levels were 7-15 times higher than in normal brain tissues in several in vivo models. 133 As another example, GSK-J4 brain access has been assessed in murine DIPG models, after being administered to mice by intraperitoneal injection. 108 After brain resection, each brainstem was dissected from the surrounding brain.…”

“…BRD4 also facilitates transcription elongation. Highly selective BET bromodomain inhibitors, such as JQ-1, 127-129 I-BET151, 130,131 I-BET762, 132 INCB054329, 126 and OTX-015, 133 have been generated to specifically target the recognition of acetylated lysine residues of BETs. Competitive binding with a BET bromodomain inhibitor blocks the binding between BRD4 and acetylated histones, leading to transcriptional inactivation (Fig.…”