Page 79 - Read Online

Tucker et al. Cancer Drug Resist 2019;2:803-12 I http://dx.doi.org/10.20517/cdr.2019.09 Page 809

THE RELATIONSHIP BETWEEN ALK AND MYCN EXPRESSION AND ITS INFLUENCE ON THE
DESIGN OF THERAPEUTIC APPROACHES
The mechanism underpinning the relationship between ALK and MYCN is being gradually further
characterized, and it is known that ALK stabilizes MYCN protein via the PI3K-Akt pathway [34,58] . This
strengthens the rationale for the current clinical study of Crizotinib combined with Temsirolimus for
patients with ALK mutant neuroblastoma. One of the primary objectives of this study is to determine
the Phase 2 dose of Crizotinib and Temsirolimus in the setting of relapsed or refractory neuroblastoma
with mutations of either ALK or MET, as the tyrosine kinase MET is an additional target of Crizotinib.
In addition to this the activity of Crizotinib will be recorded alongside pharmacodynamic analysis of
biomarkers for PI3K/AKT/mTOR in platelet rich plasma samples and paired tumor samples collected
through the course of treatment (ITCC053).

Both wild type ALK and ALK mutant species are able to stimulate the transcription of MYCN in
[59]
neuroblastoma and neuronal cell lines . Most recently the transcriptional mediator between ALK and
[60]
MYCN has been identified as “HMG-box transcription factor 1” (HBP1) . HBP1 was previously identified
[61]
as a negative regulator of MYCN activity , and also as a component of the ALK-77 gene signature
[45]
described by Lambertz et al. . Further to this, it is now determined that mutant ALK negatively regulates
HBP1 through the PI3K-Akt-Foxo3a signaling axis, allowing specific discussion of further targeted
combination therapies which should be investigated with a view to disrupting this pathway to the benefit
of these ultra-high-risk neuroblastoma patients. To this end, preclinical evidence of synergy has already
been presented for several combinations, including the PI3K inhibitor NVP-BEZ235 with the BET-
Bromodomain inhibitor, JQ1, allowing for upregulation of HBP1 and suppression of MYCN transcription
simultaneously.

Whilst it is generally acknowledged that combination therapy will be required to see durable clinical
responses, the difficulties associated with moving preclinical combinations to the clinic have led researchers
to investigate the potential of dual inhibitors for high-risk patient populations. In particular, the Polo-
like kinase 1 (PLK-1) inhibitor BI-2536, which already had low-nanomolar IC activity against BRD4, has
50
[62]
been re-designed to have additional activity against mutant ALK F1174L . Through a series of chemical
modifications to the structure, an initial set of dual inhibitors has been created, which retain their activity
against BRD4, reduce their specificity for PLK-1 and increase their activity and selectivity for the mutant
ALK ATP-binding pocket. Rationalizing further these compounds within the in vivo preclinical setting,
using a panel of validated neuroblastoma models, will provide a compelling case for these compounds to
progress into clinical studies.

CONCLUSION
Finding a targeted therapy for MYC-activated tumors, including neuroblastoma, has provided an
insurmountable challenge for cancer researchers for many years. However, as more is understood about
the transcriptional control of MYC expression, within the context of our greater appreciation of the global
control of gene expression, it is now highly likely that selective compounds will make their way from bench
to bedside. The opportunity to manipulate ALK activity in neuroblastomas is complicated by the specificity
of individual ALK mutants for available compounds. However, the progression towards innovative trial
designs incorporating personalized genomic medicine and pharmacodynamic markers will undoubtedly
improve the translational outcomes.

DECLARATIONS
Authors’ contributions
Manuscript writing: Tucker ER, Poon E