Zenith Epigenetics did not respind to invitations in this one.  ?! Why? 

European Journal of Cancer

Highlights

Abstract

Keywords

1. Introduction

The fifth multi-stakeholder Paediatric Strategy Forum on epigenetic modifiers, organised by ACCELERATE [1] in collaboration with the European Medicines Agency (EMA) with participation of the US Food and Drug Administration (FDA), agreed that there was a need for a dedicated meeting focused on prioritising the multiple bromodomain and extra-terminal (BET) inhibitors in clinical development that could potentially be evaluated in children with cancer [2].

The BET family of proteins consists of four members (BRD2, BRD3, BRD4 and BRDT) that regulate chromatin structure and gene expression through binding to acetylated lysine residues on histone tails, which is critical in regulating transcription [3]. Each BET protein contains tandem dual bromodomains (BDs), which are structurally similar between all four family members. The BET family is one of the most prominent transcriptional vulnerabilities in human cancer and therefore is an attractive epigenetic therapeutic target.

Based on biology and pre-clinical data, BET inhibitors have at least three roles in paediatric malignancies: NUT (nuclear protein in testis) carcinomas [4], MYC/MYCN-driven malignancies [[5], [6], [7], [8]] and fusion-driven cancers [[9], [10], [11], [12], [13]]. NUT carcinomas are the archetype of a BET-driven malignancy, with BRD4 and BRD3 fusions characteristic of this disease. There is controversy relating to the role of BET inhibitors in malignancies other than those driven by BRD3/BRD4 fusions [[14], [15], [16]]. It is uncertain if the concentrations necessary to achieve a biological effect in vivo in other cancers can be achieved in clinical practice due to toxicity, notably thrombocytopenia. As a result, in clinical trials, in adults to date, pan-BET inhibitors have been challenging to administer and monotherapy has generally resulted in only modest anti-tumour activity [[14], [15], [16], [17], [18], [19], [20], [21], [22], [23]].

Although BET inhibitors have been in clinical trials in adults since 2012, the first-in-child study only opened in 2019 [24]. In July 2020, there were at least 10 pan-BET inhibitors in clinical development (a number of others have been discontinued), and the relevant paediatric population is not large enough to accommodate clinical trials of all these BET medicinal products.

The consensus of the broader Paediatric Strategy Forum on epigenetic modifiers was that the future focus should be on BET inhibitors with a broader therapeutic index (facilitating combination treatment strategies), BET inhibitors with improved blood–brain barrier penetrance, and second-generation BET inhibitors with selective inhibition of the BDII bromodomain [2]. The aim of this follow-up meeting dedicated solely to BET inhibitors was to develop further a consensus, between biopharmaceutical companies with publicly recognised BET inhibitor development plans, academic researchers and patient advocates, about the development of BET inhibitors including prioritisation and their specific roles.

The meeting was held virtually over 4 h on 10th July 2020. As an introduction, an overview of the biological rationale for BET inhibitors in paediatric malignancies, relevant pre-clinical data and early clinical studies were presented. This introduction was followed by presentations by invited companies of their adult and paediatric plans, pharmacological and clinical information on nine compounds being developed as BET inhibitors. This provided a basis for a strategic discussion, overall conclusions and final consensus recommendations.

There were 47 participants: 15 academic experts; 20 representatives from eight companies with publicly recognised BET inhibitor development plans (BMS/Celgene, Boehringer Ingelheim, Constellation Pharmaceuticals, AstraZeneca, Incyte, Plexxikon, Developmental Therapeutics Consortium and Abbvie); four patient advocates (Andrew McDonough B+ Positive Foundation, Children's Cancer Cause, Coalition Against Childhood Cancer, Solving Kids' Cancer); six regulators from the FDA and EMA as observers; and two organisers. GlaxoSmithKline was initially intending to participate, but their product (molibresib) has been discontinued. Zenith Epigenetics did not respond to invitations.

2. Paediatric cancer