Investigational BET bromodomain protein inhibitors in early stage clinical trials for acute myelogenous leukemia (AML)

ABSTRACT

Introduction: Acute myelogenous leukemia (AML) is a heterogeneous group of malignancies driven by genetic mutations and deregulated epigenetic control. Relapse/refractory disease remains frequent in younger patients and even more so in older patients, including treatment with epigenetic drugs in this age group, mainly with hypomethylating agents. New treatment strategies are urgently needed. The recent discovery that epigenetic readers of the bromodomain (BRD) and extraterminal (BET) protein family, are crucial for AML maintenance by transcription of oncogenic c-MYC lead to rapid development of BET inhibitors entering clinical trials.

Areas covered: We provide a critical overview using main sources for the use of BET inhibitors in AML treatment. Limits of this treatment approach including resistance mechanisms and future directions including development of new generation BET inhibitors and combination strategies with other drugs are detailed.

Expert opinion: BET inhibitors were expected to overcome limits of conventional treatment in patients as impressive in vitro data emerged recently in well-characterized AML subsets, including those associated with poor risk characteristics in the clinic. Nevertheless single activity of BET inhibitors appears to be modest and resistance mechanisms were already identified. BET inhibitors with alternative mechanisms of action and/or combination strategies with epigenetic drugs should be tested.

KEYWORDS:

• AML
• BET inhibitors
• epigenetics
• c-MYC
• OTX015 (MK-8628)

Article Highlights

• Chemo resistance of AML patients remain a frequent observation, after currently available treatment strategies, such as intensive chemotherapy, hematopoietic stem cell transplantation or hypomethylating agents

• It was recently shown that BET proteins link deregulated epigenetic events to aberrant transcription of oncogenes in AML and that they are promising druggable targets

• Small molecules which targets BET proteins binding to histones, so called BET inhibitors, most of them being benzodiazepine derivates have already entered clinical trials mostly in relapsed or refractory AML patients

• Fully published clinical reports of early phase trials for BET inhibitors in AML are limited to the OTX015 (MK-8628) inhibitor. Only modest activity was observed in enrolled AML patients in this trial, most of them with relapsed or refractory disease. It seems therefore too early to comment the possible clinical activity of other BET inhibitors in development.

• Developments of novel approaches include next generation bivalent BET inhibitors, PROTAC mediated BRD4 degraders and combinations with other epigenetic targeting drugs. Development of robust target assays, currently lacking, are also needed to better guide the use of BET inhibitors in AML.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.