Potent Activity of the Bromodomain Inhibitor OTX015 in Multiple Myeloma

Abstract

Several studies demonstrate that the bromodomain inhibitor OTX015 has an antitumor activity in cancers. However, translation of these data to molecules suitable for clinical development has yet to be accomplished in multiple myeloma (MM). Here, we identified genes and biologic processes that substantiated the antimyeloma activity of OTX015 with global transcriptomics. OTX015 exerted a strong antiproliferative effect and induced cell cycle arrest in vitro. Gene expression profiling uncovered that OTX015 targeted NF-κB, EGFR, cell cycle regulation, and the cancer proliferation signaling pathway. Gene expression signatures displaying various levels of sensitivity to OTX015 were also identified. The data also showed that oral administration of OTX015 displayed significant antitumor activity in the mice model of disseminated human myeloma. In addition, our study provided the first evidence and rationale that OTX015 could promote osteoblast differentiation of mesenchymal stem cells (MSCs) and inhibited osteoclast formation and resorption in vivo experiments. Herein our results expanded the understanding of the mechanism for BET inhibitors OTX015 in MM. Our study provided an impressive basis for the clinical application of the novel antimyeloma agent OTX015 and uncovered signaling pathways that may play key roles in myeloma cell proliferation.

MYC inhibitors in multiple myeloma

“…The first compound to show this effect was JQ1, a BETi widely used in in vitro studies. JQ1 significantly downregulated MYC expression, causing a reduction in tumor burden and extending the overall survival in a MM mouse model [105] . Several second- generation BETis with improved properties (e.g., superior oral or intraperitoneal bioavailability, distinct chemical structure, etc.)…”

“…OTX015 was recently demonstrated to have a considerable antitumor effect in a myeloma xenograft model that recapitulates the disseminated form of the human disease, extending the overall survival of mice [ 106 ] . The authors found that MYC levels were downregulated in two myeloma cell lines, which suggested that MYC itself could be a pharmacodynamic (PD) marker of BET inhibition, although its usefulness would be limited to hematologic tumors [ 107 ] .…”

Achieving clinical success with BET inhibitors as anti-cancer agents

“…In preclinical studies, OTX015 showed efficacy against haematological malignancies including B-cell lymphoma, multiple myeloma and some solid types of cancer such as neuroblastoma and mesothelioma. 47,[51][52][53] The average doses for early BETi such as JQ1, I-BET762, I-BET151 and OTX015 generally ranged between 300 nM to1 µM in vitro and 30-50 mg/kg in murine models of cancer. 23,[54][55][56][57] While these compounds differ from next-generation molecules in their pharmacokinetics, it is unclear that preclinical findings using such high doses of drug could predict anti-tumour responses in patients at tolerable doses.…”

The paradigm of drug resistance in cancer: an epigenetic perspective

“…Due to the low oral bioavailability and short half-life of JQ1, it has not been used in clinical trials [ 307 ]. OTX015 (Birabresib), another small molecule similar to JQ1, inhibits BRD2, BRD3 and BRD4 supports oral administration and has been reported to display anti-cancer effects in preclinical studies of drug-resistant neuroblastoma [ 264 ], mesothelioma [ 265 ], multiple myeloma [ 266 ], and B-cell lymphoma [ 267 ]. I-BET62 is orally bioavailable and has shown efficacy as an anti-tumor agent in preclinical models, including multiple myeloma [ 268 ], pancreatic adenocarcinoma [ 269 ], and neuroblastoma [ 270 ].…”