Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study

Berthon, Céline; Raffoux, Emmanuel; Thomas, Xavier; Vey, Norbert; Gomez‐Roca, Carlos; Yee, Karen; Taussig, David; Rezai, Keyvan; Roumier, Christophe; Hérait, Patrice; Kahatt, Carmen; Quesnel, Bruno; Michallet, Mauricette; Récher, Christian; Lokiec, François; Preudhomme, Claude; Dombret, Hervé

doi:10.1016/s2352-3026(15)00247-1

Cited by 368 publications

(305 citation statements)

References 29 publications

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“…288 Early trial results with these inhibitors show durable responses and appear promising. 289,290 Other examples are targeting of BRD4, a member of the BET family of bromodomain epigenetic readers, 291 or of KMT2A (MLL)-rearranged leukemias. 292,293 In a randomized trial conducted in patients with relapsed and refractory AML, the topoisomerase II inhibitor vosaroxin in combination with IDAC demonstrated a small survival benefit in patients older than 60 years (7.1 vs 5.0 months); a benefit was not shown in younger patients, potentially due to the higher transplant rate (45.8% ,60 years vs 20.2% $60 years).…”

Section: Novel Therapiesmentioning

confidence: 99%

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

Döhner

Estey

Grimwade

et al. 2017

Blood

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4,458

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The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease

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Section: Novel Therapiesmentioning

confidence: 99%

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

Döhner

Estey

Grimwade

et al. 2017

Blood

Self Cite

4,458

4,984

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“…another BET bromodomain inhibitor currently being tested in clinical trials for various tumor entities (28,29) (Supplementary Figure 4).…”

Section: Combined Targeting Of Bcl-2 and Bet Bromodomain Proteins Inmentioning

confidence: 99%

Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia

et al. 2017

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Inhibition of anti-apoptotic BCL-2 has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax . In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant loss of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.Leukemia accepted article preview online, 11 January 2017. doi:10.1038/leu.2017.10. This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG are providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply. Conflict of interestThe authors declare no conflict of interest.© 2017 Macmillan Publishers Limited. All rights reserved.3 AbstractInhibition of anti-apoptotic BCL-2 has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax . In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant loss of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2.Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.

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“…Recently, BRD4 has become an attractive target for cancer therapy, as specific small-molecule BRD4/BET inhibitors, such as JQ1 and OTX015/MK-8628, are currently in clinical trials for cancer (ClinicalTrials. gov identifier: NCT01713582) (11)(12)(13). In ovarian cancer cell lines and patient-derived xenograft model systems of HGSC, suppression of BRD4 using the small-molecule BET inhibitors JQ1 and/or I-BET151 exerted robust antitumor effects (7,10), thereby providing a rationale for further investigating genomic alterations of the BRD4 pathway and the clinical benefits of BRD4-specific inhibitors in pelvic HGSC.…”

Section: Introductionmentioning

confidence: 99%

Amplification of the NSD3‑BRD4‑CHD8 pathway in pelvic high‑grade serous carcinomas of tubo‑ovarian and endometrial origin

Jones

Lin

2017

mol clin onc

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Abstract. Identification of novel therapeutics in pelvic high-grade serous carcinoma (HGSC) has been hampered by a paucity of actionable point mutations in target genes. The aim of the present study was to investigate the extent of amplification of the therapeutically targetable NSD3-CHD8-BRD4 pathway in pelvic HGSC, and to determine whether amplification is associated with worse prognosis. The Cancer Genome Atlas (TCGA) ovarian and endometrial cancer cohorts were retrospectively analyzed via online data-mining tools to test the association of NSD3, CHD8 and BRD4 genomic alterations with survival of pelvic HGSC patients. It was demonstrated that amplification of the NSD3-CHD8-BRD4 pathway in the ovarian HGSC cohort (observed in 18% of the cases, 88/489) was significantly associated with worse overall and progression-free survival compared with non-amplified cases. In addition, amplification of NSD3, CHD8 and BRD4 also occurred in 9% (21/232) of overall endometrial cancer TCGA cases, which was associated with worse overall survival. In the endometrial cancer TCGA cohort, NSD3, CHD8 and BRD4 amplification occurred specifically in the serous carcinoma (25%, 13/53) and 'serous-like' copy number high endometrial carcinoma (33%, 20/60) subgroups, compared with the polymerase e (0%, 0/17), microsatellite instability high (0%, 0/65) or low copy number (1%, 1/90) subgroups. These findings support the hypothesis that amplification of the NSD3-BRD4-CDH8 axis is frequent in pelvic HGSC of both ovarian and endometrial origin, and that this pathway is potentially targetable in a subset of HGSC patients.

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Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study

Cited by 368 publications

References 29 publications

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia

Amplification of the NSD3‑BRD4‑CHD8 pathway in pelvic high‑grade serous carcinomas of tubo‑ovarian and endometrial origin

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