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Page 806 Tucker et al. Cancer Drug Resist 2019;2:803-12 I http://dx.doi.org/10.20517/cdr.2019.09

Inhibition of the bromodomain and extraterminal domain (BET) family has also been shown to down-
[19]
regulate MYCN transcription in MYCN-amplified neuroblastoma . Bromodomain-4 (BRD4), a member
of this family, interacts with the positive transcription elongation factor b, and together they are recruited
to promoters to phosphorylate RNA polymerase II, particularly at the promoters of genes associated with
super-enhancer regions, including MYC [20,21] . In an effort to support the progression of BRD4 inhibitors
to the pediatric clinic for neuroblastoma, OTX015, an orally-administered compound, was studied in a
[22]
panel of preclinical neuroblastoma models . This molecule was found to have specific activity against
MYCN target genes, which correlated with high level MYCN expression and MYCN amplification in a
panel of neuroblastoma cell lines. The conclusions from a recent phase I/II study with the BET inhibitor,
GSK525762, which allowed for the inclusion of neuroblastoma patients over the age of 16, are awaited
(NCT01587703).

Cyclin dependent kinase 7 (CDK7) and cyclin dependent kinase 9 (CDK9) play a key role in the
transcriptional cycle of RNA polymerase II. Inhibition of CDK7 or CDK9 selectively kills tumor cells, by
[23]
targeting the super-enhancer clusters of the genome that are associated with MYCN regulation . In the
laboratory, many mono-or pan-CDK inhibitors have been reported to display robust anti-tumor effects
either by down-regulating MYCN protein or shutting down its transcriptional activity in neuroblastoma
[24]
(THZ1, CYC065 and dinaciclib) or other cancers (SY-1365, BAY1143572) . Although many of them are
undergoing clinical evaluation in adults, pediatric trials in neuroblastoma have not yet commenced.

Genetic screens have been used to identify genes that are synthetic lethal to MYCN amplification/
overexpression, leading to preclinical evaluation of many new agents in neuroblastoma. One of such agent
[25]
is CCT244747 following the characterization of synthetic lethal interaction between CHK1 and MYCN .
Another example is AT7519 following the finding that inactivation of CDK2 is synthetically lethal to
[26]
MYCN in neuroblastoma cells . These new approaches may identify many new targets and agents that are
effective in treating neuroblastoma, especially when used in combination with established therapeutics .
[27]
MYCN amplification and overexpression has also been found in a further small subset of pediatric and
adult cancers such as medulloblastoma, retinoblastoma, glioma, lung, pancreas, prostate and hematological
cancers. Some effort has been made in the recent years to inhibit MYCN in these tumors, however, most
of them were adapted from approaches that have been identified in research conducted originally in
[28]
neuroblastoma .

DIRECT AND COMBINATORIAL THERAPEUTICS FOR ALK-MUTANT NEUROBLASTOMA
Mutations of the tyrosine kinase ALK were firstly identified in neuroblastoma as the main cause of rare,
familial cases of the disease [29,30] . In hereditary neuroblastoma, a mutation at the R1275 locus of ALK can
[31]
be treated using the first-generation ALK inhibitor, Crizotinib . In non-hereditary cases of neuroblastoma
somatic ALK mutations or amplifications have been shown to be associated with a poor prognosis, for
which Crizotinib treatment is often not efficacious [2,30,32,33] . ALK mutations are found in around 9% of all
[2]
neuroblastomas at diagnosis, with the incidence increasing to 14% in the high-risk subtype . In contrast
to the situation with MYCN amplification, ALK is the first kinase identified as a driver in neuroblastoma
with real potential as a tractable therapeutic target, due to the number of inhibitors already available. If
MYCN amplification and an ALK mutation are found concomitantly, this is associated with an ultra-high-
[3]
risk molecular phenotype . Constitutive activity of ALK, which activates signaling via PI3K/Akt, MAPK,
ERK5 and JAK/STAT, leads to the transcriptional up-regulation of MYCN and MYCN protein stabilization,
thus compounding the aggressive nature of this cohort of tumors [34-36] [Figure 1].

The availability of later-generation ALK-targeted therapeutics has led to a unique situation for pediatric
neuroblastoma patients. There are now open trials for pediatric patients with either Ceritinib or Lorlatinib.